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[Relationships between the brain and the immune system]

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Abstract

The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).

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... Almost all the immune organs are intimately connected with the CNS through peripheral nervous system (PNS). Look at what Dantzer and Wollman (2003) tell about the relationship in their article: ...
... Recent advances in the study of the interrelationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. [11] They further explained how the lymphoid organs are connected with the autonomic nervous system and how the immune functions are regulated by the membrane receptors which bind to the neurotransmitters and neuropeptides [ Figure 12]. Immune functions such as cell proliferation, chimiotactism, specific immune responses and many other vital ones are activated and regulated by the integrated neuroendocrine-immune network. ...
... Immune functions such as cell proliferation, chimiotactism, specific immune responses and many other vital ones are activated and regulated by the integrated neuroendocrine-immune network. In an article, "Relationships between the brain and the immune system," Dantzer and Wollman (2003) further narrate: ...
... Es de este concepto -en el que el SNC, el SNS y el Sistema Nervioso Periférico (SNP) modulan al SI-que surge la teoría de la etiología del estrés. La evidencia resulta de la activación de las funciones inmunológicas como la proliferación celular, el quimiotactismo y respuestas inmunológicas específicas, a partir de la amplia inervación anatómica del SNS a los órganos linfoides, de la regulación mediante neurotransmisores adrenérgicos a través de rutas neuronales, de la activación de las células del SI mediante receptores de membrana para neuropéptidos y neurotransmisores como la noradrenalina, y de hormonas endocrinas a través del eje hipotálamo-hipófisis-glándula adrenal [56][57][58] . En síntesis, el estrés genera una inmunosupresión regulada por los glucocorticoides secretados por las glándulas suprarrenales, por las catecolaminas y neuropétidos secretados por las terminaciones nervio-sas del SNS y la médula de la glándula suprarrenal, hormonas endocrinas liberadas por la hipófisis y señales peptídicas autocrinas y paracrinas producidas por los monocitos y macrófagos, dentro de las cuales se incluyen las citoquinas proinflamatorias [56][57][58] . ...
... La evidencia resulta de la activación de las funciones inmunológicas como la proliferación celular, el quimiotactismo y respuestas inmunológicas específicas, a partir de la amplia inervación anatómica del SNS a los órganos linfoides, de la regulación mediante neurotransmisores adrenérgicos a través de rutas neuronales, de la activación de las células del SI mediante receptores de membrana para neuropéptidos y neurotransmisores como la noradrenalina, y de hormonas endocrinas a través del eje hipotálamo-hipófisis-glándula adrenal [56][57][58] . En síntesis, el estrés genera una inmunosupresión regulada por los glucocorticoides secretados por las glándulas suprarrenales, por las catecolaminas y neuropétidos secretados por las terminaciones nervio-sas del SNS y la médula de la glándula suprarrenal, hormonas endocrinas liberadas por la hipófisis y señales peptídicas autocrinas y paracrinas producidas por los monocitos y macrófagos, dentro de las cuales se incluyen las citoquinas proinflamatorias [56][57][58] . ...
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El estrés se reconoce como un proceso fisiopatológico que ocurre cuando un individuo se enfrenta a demandas ambientales que sobrepasan sus recursos, haciendo que el cuerpo emita una respuesta, la cual implica la activación fisiológica y cognitiva del cuerpo, (sistema nervioso central, sistema endocrino y sistema inmunológico), para actuar de manera más rápida y enérgica a las exigencias de la situación, por lo tanto esta respuesta es de naturaleza sistémica y trae una serie de consecuencias metabólicas tales como aumento de la síntesis de esteroides y un estado de inflamación crónica, por lo que el estrés psicológico se considera un factor de riesgo para el desarrollo de enfermedades crónicas. El estrés psicológico en un campo académico, se denomina estrés académico.
... The relationship between brain injury and excessive systemic inflammation has previously been reported in other acute diseases [62][63][64]. The systemic inflammatory signals are purported to affect brain regions via either the humoral/ neural pathways (via a compromised BBB) or via the activation of the vagus nerve [65][66][67]. For instance, systemic levels of TNFa have been reported to mediate brain injury processes after TBI and stroke [68] and inflammation in astrocytes [69]. ...
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Objective Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. Methods Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs—including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs—including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women. Results Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly ( p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly ( p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. Conclusion The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.
... In both animal and human models, research in psychoneuroimmunology has revealed interactions between the central nervous system (CNS), HPA axis, and immune system functioning via multiple pathways (Ader et al., 1990;Dantzer and Wollman, 2003;Dantzer, 2017;Marques-Deak et al., 2005). First, activity in the ANS, originating in various nuclei in the brain stem, modulate inflammatory responses in the periphery. ...
Article
In the past century, medical progress has helped increase life expectancy and improve health outcomes more generally. Despite this progress, psychiatric disorders—especially affective disorders including depressive and anxiety disorders—are quite common and have been linked to dysfunction in endocrine and immune systems. In this review, we discuss neurobiological correlates of emotion regulation strategies and their effects on mental and physical health. Some of these correlates, namely sub-regions of prefrontal cortex, also play a key regulatory role in autonomic, endocrine, and immunological processes. Given this functional overlap, we propose a novel neuro-immuno-affective framework that targets improving emotion regulation, in order to: (1) reduce negative affect associated with depressive and/or anxiety disorders; and (2) alter endocrine and immune system functioning (e.g., reduce inflammation)—via changes in activity within (and connectivity between) brain systems that support (successful) emotion regulation. We conclude by arguing that such a framework can be adapted for psychiatric treatment protocols that holistically incorporate neural and immunological biomarkers to promote mental and physical health.
... The immune system encompasses the elements in our body that have the thankless job of keeping the body healthy, protecting it from disease (Steinman 2004). The immune system fights against outside factors like pathogens, as well as internal diseases such as cancerous cells with constant vigil, utilizing immune cells, molecules, and immune organs, in a structure that is only second to the nervous system in complexity (Steinman 2004;Dantzer and Wollman 2003;Chaplin 2010). The primary function of the immune system is to prevent infectious diseases. ...
Chapter
The use of Mesenchymal Stem Cells (MSCs) in the treatment of diseases where immunomodulation impacts therapy is increasing steadily. Recent studies aim to achieve effective use of MSCs in treatment of Graft versus Host Disease (GvHD), Crohn’s disease and organ transplantations. The molecular mechanisms governing immunomodulatory properties of MSCs have not been fully understood, although current studies are indicating progress. Especially, in vitro studies and animal models provide a major contribution to our knowledge in clinical use of MSCs. The immunosuppressive and immune-enhancer properties of MSCs are –typically- determined with respect to type and concentrations of soluble molecules found in their physiological environment. In mammals the immune system protects the organism -not only- from certain microorganisms, but also from any entity that it recognizes as foreign, including its own cells when it is received as a threat. This protection can sometimes occur by increasing the number of immune cells and sometimes by suppressing a pathologically hyper-induced immunological response. In particular, realization of the bi-directional effect of MSCs on immune cells has placed substantial emphasis on this area of research. This chapter focuses on the interaction of MSCs with the immune cells, the bilateral role of these interactions, and whether studies that aim to understand these interactions can yield promising results in terms of developing improved use of MSCs in treatment.
... La ansiedad, caracterizada de forma general como la preocupación, excesiva e incontrolable, ante el estrés académico se ha asociado con diferentes signos y síntomas físicos que eventualmente podrán llevar al individuo a un trastorno depresivo, debido a que estrés, ansiedad y depresión comparten ciertos factores biológicos, dentro de los cuales se encuentran la activación de la respuesta inflamatoria. El aumento de los niveles de proteínas de fase aguda en sangre como la PCR [de acuerdo a los valores de la OMS en bajo riesgo (>1.0 mg/L), riesgo medio (1.0-3.0 mg/L) y alto riesgo (>3.0 mg/L)], está siendo el foco de investigación epidemiológica de comorbilidades (enfermedades mentales y sistémicas) durante los últimos 17 años, mediante la articulación del eje hipotálamo-hipófisis-glándulas suprarrenales, el sistema nervioso simpático y la respuesta inmunológica [32][33][34][35][36] . La ansiedad, implicada en la respuesta emocional anticipada ante una situación de estrés situacional y transitoria, cuenta con ciertos niveles de adaptación -en muchos casos considerados normales e inútiles-, que permiten mejorar el rendimiento, de tal forma que a mayor actividad, mayor ansiedad y mayor rendimiento. ...
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Stress is recognized as a pathophysiological process that occurs when an individual is faced with environmental demands that exceed their resources, making the body emits a stress response. This response involves the activation of physiological and cognitive body (central nervous system, endocrine system and immune system), to act faster and more energetic the situation so demands, thus this response is systemic in nature and brings a series of metabolic consequences such as increased steroid synthesis and a state of chronic inflammation, so that psychological stress is considered a risk factor for the development of chronic diseases. Psychological stress in an academic field, is called academic stress. Medical students are exposed to a greater number of stressors, which are inherent in his career, and predisposes them to have different levels of stress.
... The skin plays an important immunological function, involving a large amount of cells in coordinating the body's response to external and internal disturbances (31). Glycoproteins termed cytokines play a major role in mediating this process. ...
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Psychodermatology study the relationship between skin and mind. The important starting point in most of the chronic skin conditions, is the psychological factor. Acute adverse events are classic triggers for these diseases. Chronic distress play an important role, especially in time of public professional and financial instability, combined with the characteristics of the personal profile of the individual. Patients suffering from chronic skin dermatoses are tense, anxious, and unable to relax. This article review the neuro-endocrine pathway in the genesis of psychodermatological conditions. The paradigm: chronic skin conditions, stress and psyche is discussed. The review is based on the data from English language literature using MEDLINE and PubMed
... Aunque las pruebas de la función de las infecciones en la incidencia y evolución de las EA son en su mayoría epidemiológicas e indirectas, los modelos en animales han demostrado la veracidad de esta hipótesis. 7,8 Dichas enfermedades se asocian con más frecuencia a los virus, y las que tienen probable causa viral son: 9 − Artropatías: virus de la leucemia de célula T humano tipo 1 (HTLV-1, por sus siglas en inglés) La infección por hepatitis viral B y C en el ser humano provoca diversas manifestaciones clínicas y su mantenimiento en el organismo está condicionado por cambios en los mecanismos de respuesta inmunitaria del huésped. 10 De igual manera, los agentes infecciosos podrían actuar como iniciadores de la aparición de una enfermedad autoinmune a través de varios mecanismos. ...
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A descriptive observational and immunological study was carried out in 42 patients with diagnosis of autoimmune disease or suspicion of this, attended at the Immunology Department of "Saturnino Lora Torres" Provincial Clinical Surgical Teaching Hospital of Santiago de Cuba, from March 2010 to May 2011, who presented with viral hepatitis or other infections, in order to demonstrate the possible association between the clinical entity and viruses. Other serums of members of renal transplantation plan, belonging to histocompatibility studies, were used because of their high incidence of hepatitis B or C (or both), and levels of autoantibodies were determined by means of the immunodiagnosis method to detect antinuclear antibodies of the indirect immunofluorescence (qualitatively), so that the influence of viruses could be identified in autoimmune processes and, simultaneously, to recover the use of this technique. The results showed 28% of antinuclear antibodies-positive cases
... Bacteria and viruses are potent activators of proinflammatory cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-6, which are key effectors of the peripheral immune response 17 and the main mediators of brain orchestrated sickness responses following infection and inflammation. 18 In the periphery these cytokines act in a cascade-like fashion, which generally involves the sequential induction of TNF-a, IL-1b and IL-6. 19 Although the cytokinedependent inflammatory response is essential in resolving infection, abnormal changes in TNF-a, IL-1b and IL-6 levels during gestation, as a result of infection, may affect fetal brain development in utero. ...
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Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.
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Thioredoxins are small ubiquitous redox proteins that are involved in many biological processes. Proteins with thiol-disulfide bonds are essential regulators of cellular redox homeostasis and diagnostic markers for redox-dependent diseases. Here, we identified and characterized the thioredoxin domain-containing protein 12 (EaTXNDC12) gene in red spotted grouper (Epinephelus akaara), evaluated transcriptional responses, and investigated the activity of the recombinant protein using functional assays. EaTXNDC12 is a 19.22-kDa endoplasmic reticulum (ER)-resident protein with a 522-bp open reading frame and 173 amino acids, including a signal peptide. We identified a conserved active motif (⁶⁶WCGAC⁷⁰) and ER retention motif (¹⁷⁰GDEL¹⁷³) in the EaTXNDC12 amino acid sequence. Relative EaTXNDC12 mRNA expression was analyzed using 12 different tissues, with the highest expression seen in brain tissue, while skin tissue showed the lowest expression level. Furthermore, mRNA expression in response to immune challenges was analyzed in the head kidney, blood, and gill tissues. EaTXNDC12 was significantly modulated in response to bacterial endotoxin lipopolysaccharide (LPS), nervous necrosis virus (NNV), and polyinosinic:polycytidylic acid (poly(I:C)) challenges in all of the tested tissues. Recombinant EaTXNDC12 (rEaTXNDC12) displayed antioxidant ability in an insulin reductase assay, and a capacity for free radical inhibition in a 2,2-diphenyl-1-picryl-hydrazyl-hydrate assay. In addition, a DNA nicking assay revealed that purified rEaTXNDC12 exhibited concentration-dependent DNA protection activity, while results from 2-hydroxyethyl disulfide and L-dehydroascorbic assays indicated that rEaTXNDC12a possesses reducing ability. Furthermore, fathead minnow (FHM) cells transfected with EaTXNDC12-pcDNA demonstrated significantly upregulated cell survival against H2O2-induced apoptosis. Collectively, the results of this study strengthen our knowledge of EaTXNDC12 with respect to cellular redox hemostasis and immune regulation in Epinephelus akaara.
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Significance: Production of pro-inflammatory and anti-inflammatory cytokines is part of the defense system that mostly microglia and macrophages display to induce normal signaling to counteract the deleterious actions of invading pathogens in the brain. Also, redox activity in the Central Nervous System (CNS) constitutes an integral part of the metabolic processes needed by cells to exert their normal molecular and biochemical functions. Under normal conditions, the formation of Reactive Oxygen and Nitrogen Species, and the following oxidative activity encounter a healthy balance with immunological responses to preserve cell functions in the brain. However, under different pathological conditions, inflammatory responses recruit pro-oxidant signals and vice versa. Aim: The aim of this manuscript is to review the basic concepts about the triggering of inflammatory and oxidative responses in the CNS. Recent advances: Diverse concurrent toxic pathways are described to provide a solid mechanistic scope for considering intervention at the experimental and clinical levels aimed to diminish the harmful actions of these two contributing factors to nerve cell damage. Critical issues: The main conclusion supports the existence of a narrow cross-talk between pro-inflammatory and oxidative signals that can lead to neuronal damage and subsequent neurodegeneration.
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The story of human life begins much beyond birth…
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It has been thought for a long time that the psychological factors play a role that contributes to predisposition, the beginning or the course of several physical diseases. Recent studies have clearly showed the existance of a link between stress and the development of many diseases. Stress is defined as a condition that occurs when an individual percieves demands from a situation that exceeds his resources and may increase the vulnerability of the organism to certain diseases, exerting an immunosuppressive effect. An updating is made on the influences of psychological stress on those diseases that are directly connected with immunological mechanisms, such as infections, autoimmune diseases and neoplasias, as well as on its effect on the cardiovascular diseases. It is stressed that opportune psychological interventions may help to modulate the response to stress and to improve the behavior of health, teaching more adaptative methods to the subjects to interpretate the challenges of life with more effective answers.
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In the last years, the study of the interaction among behaviour, neural and endocrine function and the immune processes, has developed an interdisciplinary research field. When the homeostatic balance in the living organisms is disturbed by deficiency or excess of stimuli, to which the organism is able to adjust, a generally multifactorial stress is produced. The interactions between the nervous system and the immune system, as well as the influences of psychological stress on immunity, both in animals and humans, are reviewed.
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The dorsal vagal complex (DVC) is the focal point of an enormous convergence of sensory afferents, descending CNS pathways, and circulating signal molecules. The static performance of the circuits in the brain stem produces timely and critical reflex control over the stomach. However, it is now apparent that the vagal reflex control circuits are not static entities functioning as simple relays between brain and gut. These brain stem circuits achieve exquisite coordination of digestive processes with ongoing and anticipated changes in behavior as a consequence of the diversity of descending CNS input. Additionally, circulating factors can cause rapid changes in brain–gut control through their direct action on brainstem vagal reflex control circuits in the CNS, as well as on the vagal afferents. A multitude of possible modulatory mechanisms exist within these circuits to guarantee speed, precision, and flexibility in the control of digestive processes. An equally large number of pathogenic factors may serve to disrupt normal gastric function through action on these same circuit elements.
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Toll like receptors (TLR) are classically known by their expression in antigen Presenting Cells (APC), where they participate in recognition of pathogen molecular patterns (PAMP), absent in host cells. However, recent studies show a broader tissue spectrum for TLR expression, being able to recognize molecules derived from injured host tissue and triggering immune, metabolic and behavioral responses typically observed in disease stages. Based on the latter observations, it is feasible to consider TLR as receptors for «danger signals» derived from exogenous and endogenous injuries and therefore as a bridge between two immunological theories; the non-infectious self recognition and the danger theory. The latter assumption has implications beyond the immune response.
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Background. The atypical endometrial hyperplasia (AEH) is considered as a precancerous process for endometrial cancer. Depending on the age the treatment strategy of patients with AEH and well differentiated adenocarcinoma can vary significantly. At a young age, and in the presence of the patient's desire to preserve reproductive function, hormone therapy by progestins preferred. In the absence of these conditions simple hysterectomy is performed or hysterectomy with appendages. However, the application of hormone therapy has a risk of relapse or insensitivity. Immunohistochemical markers (IHCMs), such as ER, PgR and others used to determine sensitivity to hormone therapy of well differentiated adenocarcinoma and AEH. However, the data for the prognostic significance of these markers are rare and contradictory. The aim of the study was to determine prognostic value of IHCMs in hormonal treatment of AEH and early endometrial cancer. Study design, materials and methods. We used biopsy samples from the 25 patients with early well differentiated adenocarcinoma of the endometrium (9 patients) and AEH (16 patients) who receive hormonal treatment from 2005 to 2012. All patients were divided into 2 groups: the 1st group with good prognosis and the 2nd group with a bad prognosis concerning initial pretreatment results of IHCMs of endometrial atypia and malignancy (PTEN, Ki-67, COX-2, RgP, ER) assayed before onset of treatment and at the 6th month after initiation of treatment. Selection criterion for good prognosis was the absence of cytologic atypia in the endometrial biopsy in 6 months after initiation of treatment (average time of observation -19 months), whereas the 2nd group with bad prognosis included patients with histologically confirmed incurability and relapses after treatment. Patients were treated by Zodalex 3.6 mg per month and intrauterine device (IUD) with levonorgestrel. Outcomes were evaluated every 3 months during 2 years: Incurability is defined as presence of cytologic atypia in the biopsy in 6 months after starting the treatment. Relapses were defined as the emersion of cytological atypia in endometrial biopsy in 3 months after stated cure. Results. The expression level of estrogen receptor is higher in a group with a good prognosis (p <0.05) and the level of COX-2 was significantly lower (p <0.05). PTEN, Ki67 and PgR demonstrated no prognostic value. Conclusions. It seems that expression patterns of ER and COX-2 before the onset of treatment in patients with early well differentiated endometrial adenocarcinoma and AEH have predictive value for hormonal treatment outcomes.
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Cervical adenocarcinomas account for a significant part of all malignant cervical neoplasms. For the past five decades, the number of glandular-originated cervical cancers increased 3,5 times as compared with squamous ones, and now reaches up to 20% of all cervical cancers. Cervical adenocarcinomas usually manifest themselves at late stages, and are remarkable for aggressive clinical behaviour. Despite of some clinical differences between various types of adenocarcinomas, still not much is known about differences in immunohistochemical features; whereas analysis of immunohistochemical characteristics and expression can give valuable data for prognosis determination in various types of neoplasms. The goal of present study is to examine clinicopathological features of 4 types of cervical adenocarcinomas and to compare the data with immunohistochemical assay results. This study was performed on archival material, which included operational and biopsy material from 48 patients with cervical adenocarcinoma. 13 of them had adenosquamous cancer, 6 – serous, 17 – endometrioid and 12 – endocervical cancer. For immunohistochemical assay, antibodies against cell-cycle proteins (р16, р21, р27, р53, Cyc D1), growth factors (EGFR, TGF-b) and proliferative marker (Ki-67) were used. Mean age of patients was 42,5 years (24 to 70 years old). No significant age differences between studied groups were detected. All adenocarcinomas types metastasised to lymphatic nodes with equal frequency. Other clinicopathological features of different types of cancers were also similar. All the cases were divided in 2 groups according to the depth of cervical wall invasion (less or more than 50%). In the first group (less than 50%), expression of p27 and Ki67 markers was high; while it was reducing with increasing depth of invasion. Thus, high values of these markers’ expression are the indirect evidence of low invasive potential of this cancer type, and so are good prognostic signs. Study of cell-cycle regulator p16 revealed significant differences between adenosquamous and serous types of cervical adenocarcinoma. Its expression was high in adenosquamous type of cancer, while it was low in serous one. Based upon these results, we believe that high expression of p16 is a good prognostic sign. Endocervical and endometrioid types of adenocarcinoma were characterized by the high expression of p27 and Ki67 markers, which is not typical for the other histological types. In this case, these proteins can be the markers of good prognosis, because of the relatively favourable clinical behavior of these types of cervical adenocarcinoma.
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It has been thought for a long time that the psychological factors play a role that contributes to predisposition, the beginning or the course of several physical diseases. Recent studies have clearly showed the existance of a link between stress and the development of many diseases. Stress is defined as a condition that occurs when an individual percieves demands from a situation that exceeds his resources and may increase the vulnerability of the organism to certain diseases, exerting an immunosuppressive effect. An updating is made on the influences of psychological stress on those diseases that are directly connected with immunological mechanisms, such as infections, autoimmune diseases and neoplasias, as well as on its effect on the cardiovascular diseases. It is stressed that opportune psychological interventions may help to modulate the response to stress and to improve the behavior of health, teaching more adaptative methods to the subjects to interpretate the challenges of life with more effective answers
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In the last years, the study of the interaction among behaviour, neural and endocrine function and the immune processes, has developed an interdisciplinary research field. When the homeostatic balance in the living organisms is disturbed by deficiency or excess of stimuli, to which the organism is able to adjust, a generally multifactorial stress is produced. The interactions between the nervous system and the immune system, as well as the influences of psychological stress on immunity, both in animals and humans, are reviewed.
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The cytokine tumor necrosis factor(alpha) (TNFalpha) is associated with a constellation of physiological and behavioral characteristics that follow in response to infection such as fever, fatigue, listlessness, loss of appetite, malaise, and tactile hypersensitivity. These responses are examples of central nervous system (CNS) functions modified by the activated immune system. Our studies have focused on the involvement of TNFalpha in CNS control of gastrointestinal function and "visceral malaise". We have demonstrated that TNFalpha can elicit gastric stasis in a dose-dependent fashion via its interaction with vago-vagal neurocircuitry in the brainstem. Sensory elements of the vago-vagal reflex circuit (i.e., neurons of the solitary tract [NST] and area postrema [AP]) are activated by exposure to TNFalpha, while the efferent elements (i.e., dorsal motor neurons of the vagus [DMN]) cause gastroinhibition. Transient exposure to low doses of TNFalpha, cause potentiated (exaggerated) NST responses to stimulation. Subsequent studies suggest that TNFalpha, presynaptically modulates the release of glutamate from primary afferents to the NST. Using immunohistochemical studies, we have observed the constitutive expression of the TNFR1 receptor on central vagal afferents and spinal trigeminal afferents in the medulla, as well as on cells and afferent fibers within the dorsal root ganglia and within laminae I and II of the dorsal horn throughout the spinal cord. The constitutive presence of these receptors on these afferents may explain why inflammatory or infectious processes that generate TNFalpha can disrupt gastrointestinal functions and cause tactile hypersensitivity. These receptors may also play a critical role in the chronic allodynia and hyper-reflexia observed after spinal cord injury or peripheral nerve damage.
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Background The possibility that life events, personality or depression can be considered risk factors for cancer has been of great interest among the lay public and doctors.
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The possibility that life events, personality or depression can be considered risk factors for cancer has been of great interest among the lay public and doctors. A critical review of different publications of meta-analyses, case-control studies and cohort studies investigating a possible relation between the onset of cancer and life events, personality disorders or depression is presented. Many studies have methodological limitations with possible bias, which may explain controversial results. We selected 32 studies from which conclusions can be drawn with the least amount of bias. Eighteen out of 32 publications whose methodology permits unbiased interpretation show no link between psychological factors and the risk of cancer. Six publications show a significant link only in one or several subgroups and four surveys, three of which were published by the same author, show an inverse relation in gynecological cancers. As for life events and breast cancer, the results are slightly in favor of a positive relation in four studies; four others showed no relation and one argues in favor of an inverse risk, which means a protective effect for this cancer. For life events and other cancers, studies show no relation, with the possible exception of cancers in women where endogenous estrogens can play a role (colon and endometrial cancers), where there is an inverse relation. No studies showed a significant relation between personality features and the risk of cancer. The studies of a possible relation between depression and cancer are controversial and no conclusion can be drawn. It cannot be confidently concluded that life events, personality features or depression play a role in the onset of cancer.
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This study attempted to determine whether differing numbers of days of repeated defeat experience altered behavior, immune measures, and neuroendocrine mediators in mice. OF1 male mice were socially stressed by repeated experiences of defeat in a sensorial contact model. Subjects exposed to nine defeats showed more stretch-attend postures and fewer active defense elements than counterparts exposed to 23 defeats. Submissive subjects with nine experiences of defeat also had a lower splenocyte proliferative response than unmanipulated controls. The proliferation index progressively increased but at a higher rate in manipulated controls than in socially stressed subjects, resulting in a significant immunosuppressive effect after 23 days of exposure to social stressors. Nine days of such exposure resulted in higher hypothalamic ratios of serotonin and dopamine to their major metabolites than in unmanipulated or manipulated controls and subjects socially stressed for 23 days. The data generally indicate that the acute social stressors (such as nine defeats) produce a profile of behavioral and physiological variables characteristic of a state of anxiety. The proliferation index was also lower after 52 days of social stress than in manipulated controls. Fluoxetine treatment appeared to have an anxiolytic effect, reducing immobility, and even seemed to protect subjects from the immune impairment and endocrine alteration caused by social stressors. The results generally provide clues that improve our knowledge of the consequences of social stressors and their possible treatment.
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Growing number of studies reveal that the brain neural network plays significant role in the short-term and long-term regulation of the cardiovascular functions. The neurons involved in the complex neurogenic control of the cardiovascular system use classical neurotransmitters and nonconventional mediators such as peptides (angiotensin II, vasopressin, natriuretic peptides, endothelins, opioids, cytokines), steroids, ouabain-like factors and gaseous compounds. Among them the neuropeptides form a group of substances arising significant interest. Thanks to wide distribution of peptidergic neurons in the central nervous system, location of peptide receptors on neurons and glial cells, versatile but frequently overlapping mechanisms of activation of the intracellular processes the neuropeptides play significant role in short-term and long-term regulation of excitability and remodeling of the neurons. In several instances they modulate effects of the classical transmitting systems involved in regulation blood pressure, heart rate, water-electrolyte balance, metabolism, stress, pain, mood and memory. Prolonged activation or inhibition of specific neuropeptide pathways frequently results in long-lasting disorders of several regulatory systems. In this review this is exemplified by overactivity of angiotensin II, vasopressin and cytokines in the brain during hypertension, heart failure and stress. Multifarious actions of angiotensin II and vasopressin, and their mutual interaction with cytokines make of these neuropeptides excellent candidates for the compounds responsible for long-term resetting of the central cardiovascular control, and forming a link between the cardiovascular diseases, stress and mood disorders.
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Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.
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Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.
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Significance In humans and genetically engineered mouse models (GEMs), the development of pancreatic ductal adenocarcinoma (PDAC) is accompanied by intimate neural–tumor interactions. Using a PDAC GEM that phenocopies the human disease, we found that many changes in peripheral and central nervous systems, indicative of injury and inflammation, arise at time points prior to overt tumor formation. Ablation of sensory neurons that innervate the pancreas, via neonatal capsaicin treatment, prevented neurogenic inflammation and delayed tumor formation. The slowing of PDAC in capsaicin-treated mice suggests the nervous system is not a bystander with respect to disease progression. Further studies are warranted to examine nervous system–tumor interactions and to identify potential targets for early detection, prevention, and treatment.
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Neuroinflammation is implicated in the pathogenesis of a wide range of neurological and neuropsychiatric diseases. For over 20 years (11)C-PK11195 PET, which aims to image the expression of the translocator protein (TSPO) on activated microglia in the brain, has been used in preclinical and clinical research to investigate neuroinflammation in- vivo in patients with brain diseases. However, (11)C-PK11195 suffers from two major limitations; low brain permeability and high non-specific and plasma binding, resulting in a low signal-to-noise ratio, and secondly the use of (11)C restricts its use to PET research centres and hospitals with an on-site cyclotron. In recent years there has been a great deal of work into the development of new TSPO-specific PET radiotracers. This has focussed on fluorinated radiotracers, which would enable wider use and improved signal-to-noise ratios. These radiotracers have been utilised in preclinical and clinical studies of a number of neurological diseases with varying degrees of success. Unfortunately, the application of these second generation TSPO radiotracers has resulted in identification of additional problems, including the discovery of a polymorphism that affects TSPO binding. In this review the developments in TSPO imaging will be discussed, with current limitations and suggestions for future directions explored.
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Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression.
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Significance Neuroinflammation is a brain immune response that is associated with neurodegenerative diseases and is primarily driven by activation of microglia, the brain’s resident macrophages. Dysfunctional microglial activation may contribute to the behavioral changes observed in neurodegenerative diseases. Upon activation, microglia express translocator protein, which can be imaged with the radiotracer [ ¹¹ C]PBR28 and positron emission tomography (PET) in the living human brain. We imaged healthy human subjects with [ ¹¹ C]PBR28 and PET before and after i.v. administration of lipopolysaccharide (LPS), a potent immune activator. LPS produced a marked increase in brain microglial activation, peripheral inflammatory cytokine levels, and self-reported sickness symptoms. This imaging paradigm can provide a direct approach to test new medications for their potential to reduce acute neuroinflammation.
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Microglial cells are the resident macrophages of the central nervous system (CNS). Besides their classical roles in pathological conditions, these immune cells also dynamically interact with neurons and influence their structure and function in physiological conditions. The neuronal chemokine fractalkine and its microglial receptor CX3CR1 are one important signaling pathway involved in these reciprocal interactions. In the present review, we will discuss recent evidence indicating that fractalkine signaling also determines several functions of microglial cells during normal CNS development. It has been known for a decade that microglial cells influence the neuronal death that normally occurs during CNS development. Surprisingly, recent evidence indicates that they can also support survival of developing neurons, control axon outgrowth, and laminar positioning of subsets of interneurons in the forebrain. Moreover, microglial cells influence the maturation of synaptic circuits at early postnatal stages: their phagocytic activity allows them to eliminate inappropriate synapses and they can also influence the functional expression of synaptic proteins by releasing mediators. Fractalkine signaling controls these functions of microglial cells in part by regulating their timely recruitment at sites of developing synapses. Finally, ongoing research suggests that this signaling pathway is also a key player in neurodevelopmental disorders.
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High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and pro-inflammatory cytokine release. HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including ischemia, traumatic brain injury, seizure and chronic ethanol use. In the present review, the unique structural and functional properties of HMGB1 will be explored including its affinity for multiple pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein glucocorticoids induce synthesis and release of HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3 inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an alarmin by inducing HMGB1, thereby preparing an organism's innate immune system (NLRP3 inflammasome priming) for subsequent immune challenges such as injury, trauma or infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges. Copyright © 2015. Published by Elsevier Inc.
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Recent studies have revealed the essential role played by nerves in tumor progression. Nerves have been shown to infiltrate the tumor microenvironment and actively stimulate cancer cell growth and dissemination. This mechanism involves the release of neurotransmitters, such as catecholamines and acetylcholine, directly into the vicinity of cancer and stromal cells to activate corresponding membrane receptors. Conversely, the secretion of neurotrophic growth factors by cancer cells drives the outgrowth of nerves in solid tumors. This reciprocal interaction between nerves and cancer cells provides new insights into the cellular and molecular bases of tumorigenesis and points to the potential utility of antineurogenic therapies. This review will discuss our evolving understanding of the cross-talk between nerves and cancer cells. Cancer Res; 75(8); 1-5. ©2015 AACR. ©2015 American Association for Cancer Research.
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Diet-induced obesity leads to devastating and common chronic diseases, fueling ongoing interest in determining new mechanisms underlying both obesity and its consequences. It is now well known that chronic overnutrition produces a unique form of inflammation in peripheral insulin target tissues, and efforts to limit this inflammation have met with some success in preserving insulin sensitivity in obese individuals. Recently, the activation of inflammatory pathways by dietary excess has also been observed among cells located in the mediobasal hypothalamus, a brain area that exerts central control over peripheral glucose, fat, and energy metabolism. Here we review progress in the field of diet-induced hypothalamic inflammation, drawing key distinctions between metabolic inflammation in the hypothalamus and that occurring in peripheral tissues.We focus on specific stimuli of the inflammatory response, the roles of individual hypothalamic cell types, and the links between hypothalamic inflammation and metabolic function under normal and pathophysiological circumstances. Finally, we explore the concept of controlling hypothalamic inflammation to mitigate metabolic disease.
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Psychological stressors cause physiological, immunological, and behavioral alterations in humans and rodents that can be maladaptive and negatively affect quality of life. Several lines of evidence indicate that psychological stress disrupts key functional interactions between the immune system and brain that ultimately affects mood and behavior. For example, activation of microglia, the resident innate immune cells of the brain, has been implicated as a key regulator of mood and behavior in the context of prolonged exposure to psychological stress. Emerging evidence implicates a novel neuroimmune circuit involving microglia activation and sympathetic outflow to the peripheral immune system that further reinforces stress-related behaviors by facilitating the recruitment of inflammatory monocytes to the brain. Evidence from various rodent models, including repeated social defeat (RSD), revealed that trafficking of monocytes to the brain promoted the establishment of anxiety-like behaviors following prolonged stress exposure. In addition, new evidence implicates monocyte trafficking from the spleen to the brain as key regulator of recurring anxiety following exposure to prolonged stress. The purpose of this review is to discuss mechanisms that cause stress-induced monocyte re-distribution in the brain and how dynamic interactions between microglia, endothelial cells, and brain macrophages lead to maladaptive behavioral responses.
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We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2(-/-) mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice. The mice receiving lymphocytes from defeated donors showed less anxiety, more social behavior, and increased hippocampal cell proliferation compared with those receiving no cells or cells from unstressed donors. Mice receiving stressed immune cells had reduced pro-inflammatory cytokine levels in the blood relative to the other groups, an effect opposite to the elevated donor pro-inflammatory cytokine profile. Furthermore, mice receiving stressed immune cells had microglia skewed toward an anti-inflammatory, neuroprotective M2-like phenotype, an effect opposite the stressed donors' M1-like pro-inflammatory profile. However, stress had no effect on lymphocyte surface marker profiles in both donor and recipient mice. The data suggest that chronic stress-induced changes in the adaptive immune system, contrary to conferring anxiety and depressive behavior, protect against the deleterious effects of stress. Improvement in affective behavior is potentially mediated by reduced peripheral pro-inflammatory cytokine load, protective microglial activity, and increased hippocampal cell proliferation. The data identify the peripheral adaptive immune system as putatively involved in the mechanisms underlying stress resilience and a potential basis for developing novel rapid-acting antidepressant therapies. Copyright © 2015 the authors 0270-6474/15/351530-09$15.00/0.
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In addition to a fundamental role in cellular bioenergetics, the purine nucleotide adenosine triphosphate (ATP) plays a crucial role in the extracellular space as a signaling molecule. ATP and its metabolites serve as ligands for a family of receptors that are collectively referred to as purinergic receptors. These receptors were first described and characterized in the nervous system but it soon became evident that they are expressed ubiquitously. In the immune system, purinergic signals regulate the migration and activation of immune cells and they may also orchestrate the resolution of inflammation (1, 2). The intracellular signal transduction initiated by purinergic receptors is strongly coupled to Ca(2+)-signaling, and co-ordination of these pathways plays a critical role in innate immunity. In this review, we provide an overview of purinergic and Ca(2+)-signaling in the context of macrophage phenotypic polarization and discuss the implications on macrophage function in physiological and pathological conditions.
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Fever is a cardinal symptom of infectious or inflammatory insults, but it can also arise from noninfectious causes. The fever-inducing agent that has been used most frequently in experimental studies designed to characterize the physiological, immunological and neuroendocrine processes and to identify the neuronal circuits that underlie the manifestation of the febrile response is lipopolysaccharide (LPS). Our knowledge of the mechanisms of fever production and lysis is largely based on this model. Fever is usually initiated in the periphery of the challenged host by the immediate activation of the innate immune system by LPS, specifically of the complement (C) cascade and Toll-like receptors. The first results in the immediate generation of the C component C5a and the subsequent rapid production of prostaglandin E2 (PGE2). The second, occurring after some delay, induces the further production of PGE2 by induction of its synthesizing enzymes and transcription and translation of proinflammatory cytokines. The Kupffer cells (Kc) of the liver seem to be essential for these initial processes. The subsequent transfer of the pyrogenic message from the periphery to the brain is achieved by neuronal and humoral mechanisms. These pathways subserve the genesis of early (neuronal signals) and late (humoral signals) phases of the characteristically biphasic febrile response to LPS. During the course of fever, counterinflammatory factors, "endogenous antipyretics," are elaborated peripherally and centrally to limit fever in strength and duration. The multiple interacting pro- and antipyretic signals and their mechanistic effects that underlie endotoxic fever are the subjects of this review. © 2014 American Physiological Society. Compr Physiol 4: 1563-1604, 2014.
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Perineural growth is a unique route of tumor metastasis that is associated with poor prognosis in several solid malignancies. It is diagnosed by the presence of tumor cells inside the neural space seen on histological or imaging evaluations. Little is known about molecular mechanisms involved in the growth and spread of tumor cells in neural spaces. The poor prognosis associated with perineural growth and lack of targeted approaches necessitates the study of molecular factors involved in communication between tumor and neural cells. Perineural growth rates, shown to be as high as 63% in head and neck squamous cell carcinoma (HNSCC), correlate with increased local recurrence and decreased disease-free survival. Here we describe the literature on perineural growth in HNSCC. In addition, we discuss factors implicated in perineural growth of cancer. These factors include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 and -4, glial cell-line derived neurotrophic factor (GDNF), the neural cell adhesion molecule (NCAM), substance P (SP), and chemokines. We also explore the literature on membrane receptors, including the Trk family and the low-affinity nerve growth factor receptor. This review highlights areas for further study of the mechanisms of perineural invasion which may facilitate the identification of therapeutic targets in HNSCC. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Significance Depression and anxiety have been linked to increased inflammation. However, we do not know if inflammatory status predates onset of disease or whether it contributes to depression symptomatology. We report preexisting individual differences in the peripheral immune system that predict and promote stress susceptibility. Replacing a stress-naive animal’s peripheral immune system with that of a stressed animal increases susceptibility to social stress including repeated social defeat stress (RSDS) and witness defeat (a purely emotional form of social stress). Depleting the cytokine IL-6 from the whole body or just from leukocytes promotes resilience, as does sequestering IL-6 outside of the brain. These studies demonstrate that the emotional response to stress can be generated or blocked in the periphery, and offer a potential new form of treatment for stress disorders.
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Since the initial cloning of fractalkine/CX3CL1, it was proposed that the only known member of the CX3C or δ subfamily of chemotactic cytokines could play some significant role in the nervous system, due to its high expression on neurons. The pivotal description of the localization of the unique CX3CL1 receptor, CX3CR1, on microglial cells, firmed up by the generation of cx3cr1(GFP/GFP) mice, opened the road to the hypothesis of some specific key interactions between microglia and neurons mediated by this pair. This expectation has been indeed supported by recent exciting evidence indicating that CX3CL1-mediated microglia-neuron interaction modulates basic physiological activities during development, adulthood and aging, including: synaptic pruning; promoting survival of neurons and neural precursors; modulating synaptic transmission and plasticity; enhancing synapse and network maturation; and facilitating the establishment of neuropathic pain circuits. Beyond playing such fascinating roles in physiological conditions, CX3CL1 signaling has been implicated in different neuropathologies. Early papers demonstrated that the levels of CX3CL1 may be modulated by various toxic stimuli in vitro and that CX3CL1 signaling is positively or negatively regulated in EAE and MS, in HIV infection and LPS challenge, in epilepsy, in brain tumors, and in other neuropathologies. In this review we focus on the experimental evidence of CX3CL1 involvement in neuroprotection and survey the common molecular and cellular mechanisms described in different brain diseases.
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The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor-mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.
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Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease. Recently, it has become evident that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult-derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6c(hi) monocytes patrol the extravascular space in resting organs, and Ly6c(lo) nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation.
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Inflammation has been implicated in the development of various psychiatric disorders, including depression. However, the neurobehavioral mechanism involved in this relationship remains elusive. This gap in knowledge may best be filled by evaluating elementary neurobehavioral units affected by inflammation rather than behavioral changes in conventional animal tests of depression. To this end the current study used a concurrent choice paradigm to evaluate inflammation-induced motivational changes. Male C57BL/6 J mice (n=27) were food restricted to between 85-90% of their free feeding weight and were trained to perform a concurrent choice task where they nose poked for grain rewards on a fixed ratio (FR) 1 schedule (low effort/low reward) and chocolate-flavored rewards on a FR 10 schedule (high effort/high reward). A counterbalanced within subjects design was used. A single intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) was used to induce peripheral inflammation. Twenty-four hours after LPS administration mice showed a reduction in the total number of nose pokes. A proportionally greater reduction in nose pokes was observed for grain, resulting in an increase in percent chocolate pellets earned. These behavioral changes cannot be explained by reduced appetite as feeding prior to the test led to a similar increase in percent chocolate pellets earned but without any decrease in responding. These results indicate that inflammation modulates incentive motivation by affecting willingness to exert effort for reward and not by reducing sensitivity to reward.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.141.
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Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNFα drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNFα drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca(2+)-permeable AMPARs. Striatal TNFα signaling appears to be adaptive in nature, as TNFα is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNFα is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions.
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Background: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). Methods: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the 'leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. Results: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. Conclusions: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.
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Significance statement: Chemotherapy-induced peripheral neuropathy persists after completion of cancer treatment in a significant subset of patients, whereas others recover. Persistent neuropathy after completion of cancer treatment severely affects quality of life. We propose that understanding how neuropathy resolves will identify novel avenues for treatment. We identified a novel and critical role for CD8(+) T cells and for endogenous IL-10 in recovery from paclitaxel-induced neuropathy in mice. Enhancing the capacity of CD8(+) T cells to promote resolution or increasing IL-10 signaling are promising targets for novel interventions. Clinically, peripheral blood CD8(+) T-cell function and/or the capacity of individuals to produce IL-10 may represent biomarkers of risk for developing persistent peripheral neuropathy after completion of cancer treatment.
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Data from clinical and preclinical studies indicate that immune dysregulation, specifically of inflammatory processes, is associated with symptoms of major depressive disorder (MDD). In particular, increased levels of circulating pro-inflammatory cytokines and concomitant activation of brain-resident microglia can lead to depressive behavioural symptoms. Repeated exposure to psychological stress has a profound impact on peripheral immune responses and perturbs the function of brain microglia, which may contribute to neurobiological changes underlying MDD. Here, we review these findings and discuss ongoing studies examining neuroimmune mechanisms that influence neuronal activity as well as synaptic plasticity. Interventions targeting immune-related cellular and molecular pathways may benefit subsets of MDD patients with immune dysregulation.
Article
Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.
Article
The peripheral autonomic nervous system (ANS) is known to regulate gene expression in primary tumours and their surrounding microenvironment. Activation of the sympathetic division of the ANS in particular modulates gene expression programmes that promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis, epithelial-mesenchymal transition and tumour invasion, and by inhibiting cellular immune responses and programmed cell death. Haematological cancers are modulated by sympathetic nervous system (SNS) regulation of stem cell biology and haematopoietic differentiation programmes. In addition to identifying a molecular basis for physiologic stress effects on cancer, these findings have also identified new pharmacological strategies to inhibit cancer progression in vivo.
Article
Preclinical evidence has suggested that sustained adrenergic activation can promote ovarian cancer growth and metastasis. The authors examined the impact of beta-adrenergic blockade on the clinical outcome of women with epithelial ovarian, primary peritoneal, or fallopian tube cancers (collectively, epithelial ovarian cancer [EOC]). A multicenter review of 1425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta-blocker use during chemotherapy and those without beta-blocker use. The median age of patients in the current study was 63 years (range, 21-93 years). The sample included 269 patients who received beta-blockers. Of those, 193 (71.7%) were receiving beta-1-adrenergic receptor selective agents, and the remaining patients were receiving nonselective beta antagonists. The primary indication for beta-blocker use was hypertension but also included arrhythmia and postmyocardial infarction management. For patients receiving any beta-blocker, the median overall survival (OS) was 47.8 months versus 42 months for nonusers (P =.04). The median OS based on beta-blocker receptor selectivity was 94.9 months for those receiving nonselective beta-blockers versus 38 months for those receiving beta-1-adrenergic receptor selective agents (P<.001). Hypertension was associated with decreased OS compared with no hypertension across all groups. However, even among patients with hypertension, a longer median OS was observed among users of a nonselective beta-blocker compared with nonusers (38.2 months vs 90 months; P<.001). Use of nonselective beta-blockers in patients with EOC was associated with longer OS. These findings may have implications for new therapeutic approaches. Cancer 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
Article
Anorexia is a common symptom in chronic illness. It contributes to malnutrition and strongly affects survival and quality of life. A common denominator of many chronic diseases is an elevated inflammatory status, which is considered to play a pivotal role in the failure of food-intake regulating systems in the hypothalamus. In this review, we summarize findings on the role of hypothalamic inflammation on food intake regulation involving hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC). Furthermore, we outline the role of serotonin in the inability of these peptide based food-intake regulating systems to respond and adapt to changes in energy metabolism during chronic disease. Copyright © 2015. Published by Elsevier Inc.
Article
Microglia are the resident macrophages of the central nervous system (CNS), which sit in close proximity to neural structures and are intimately involved in brain homeostasis. The microglial population also plays fundamental roles during neuronal expansion and differentiation, as well as in the perinatal establishment of synaptic circuits. Any change in the normal brain environment results in microglial activation, which can be detrimental if not appropriately regulated. Aberrant microglial function has been linked to the development of several neurological and psychiatric diseases. However, microglia also possess potent immunoregulatory and regenerative capacities, making them attractive targets for therapeutic manipulation. Such rationale manipulations will, however, require in-depth knowledge of their origins and the molecular mechanisms underlying their homeostasis. Here, we discuss the latest advances in our understanding of the origin, differentiation, and homeostasis of microglial cells and their myelomonocytic relatives in the CNS. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
Article
Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p < 0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p < 0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d = −0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
Article
Children who experience chronic stressors are vulnerable to emotional and physical health problems across the lifespan. This phenomenon raises questions for scientists and clinicians alike. How does adversity get under the skin of the developing child? Through what mechanisms does it confer vulnerability to a heterogeneous set of mental and physical illnesses? And how does it instantiate risk across different life stages, engendering vulnerability to conditions that develop shortly after stressor exposure-like depression-and conditions that manifest decades later, like heart disease? Although answers to these questions have started to emerge, research has typically focused on single diseases or organ systems. To understand the plethora of health problems associated with childhood adversity, we argue that the field needs a second generation of research that recognizes multidirectional transactions among biological systems. To help facilitate this process, we propose a neuroimmune network hypothesis as a heuristic framework for organizing knowledge from disparate literatures and as a springboard for generating integrative research. Drawing on existing data, we argue that early-life adversity amplifies crosstalk between peripheral inflammation and neural circuitries subserving threat-related, reward-related, and executive control-related processes. This crosstalk results in chronic low-grade inflammation, thereby contributing to adiposity, insulin resistance, and other predisease states. In the brain, inflammatory mediators act on cortico-amygdala threat and cortico-basal ganglia reward, circuitries in a manner that predisposes individuals to self-medicating behaviors like smoking, drug use, and consumption of high-fat diets. Acting in concert with inflammation, these behaviors accelerate the pathogenesis of emotional and physical health problems. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Article
Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.
Article
Objective: Density of sympathetic nerve fibers decreases in inflamed arthritic tissue tested by immunoreactivity towards tyrosine-hydroxylase (TH, catecholaminergic key enzyme). Since sympathetic nerve fibers may change phenotype from catecholaminergic to cholinergic (example: sweat glands), loss of nerve fibers may relate to undetectable TH. We aimed to investigate possible catecholaminergic-to-cholinergic transition of sympathetic nerve fibers in synovial tissue of animals with arthritis, and patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and we wanted to find a possible transition factor. Methods: Nerve fibers were detected by immunofluorescence towards TH (catecholaminergic) and vesicular acetylcholine transporter (cholinergic). Co-culture experiments with sympathetic ganglia and lymphocytes or osteoclast progenitors were designed to find stimulators of catecholaminergic-to-cholinergic transition (including gene expression profiling). Results: In mouse joints, an increased density of cholinergic relative to catecholaminergic nerve fibers appeared towards day 35 after immunization, but most nerve fibers were located in healthy joint-adjacent skin or muscle and almost none in inflamed synovial tissue. In humans, cholinergic fibers are more prevalent in OA synovial tissue than in RA. Co-culture of sympathetic ganglia with osteoclast progenitors obtained from healthy but not from arthritic animals induced catecholaminergic-to-cholinergic transition. Osteoclast mRNA microarray data indicated that leukemia inhibitory factor (LIF) is a candidate transition factor, which was confirmed in ganglia experiments, particularly, in the presence of progesterone. Conclusion: In humans and mice, catecholaminergic-to-cholinergic sympathetic transition happens in less inflamed tissue but not in inflamed arthritic tissue. Under healthy conditions, presence of cholinergic sympathetic nerve fibers may support the cholinergic anti-inflammatory influence recently described.
Article
Abstract Complex interactions between biological, behavioral and environmental factors are involved in mediating individual differences in health and disease. In this review, we present evidence suggesting that increased vulnerability to infectious disease may be at least, in part, due to long-lasting effects of early life psychosocial adversities. Studies have shown that maternal psychosocial stress during pregnancy is associated with long lasting changes in immune function and disease resistance in the offspring. Studies further indicated that harsh environmental conditions during the neonatal period may also cause lasting changes in host response to infectious disease. Although the mechanisms involved in these effects have not been fully examined, several potential mediators have been described, including changes in the development of the offspring hypothalamic-pituitary-adrenal axis, alterations in epigenetic pathways, stress-related maternal health risk behavior and infection during pregnancy. Although there are ample literature indicating that perinatal psychosocial stress increases vulnerability to disease, other reports suggest that mild predictable stressors may benefit the organism and allow better coping with future stressors. Thus, understanding the possible consequences of perinatal adversities and the mechanisms that are involved in immune regulation is important for increasing awareness to the potential outcomes of early negative life events and providing insight into potential therapies to combat infection in vulnerable individuals.
Article
The antirheumatic effects of the adrenal cortical hormone, cortisone, and of the pituitary adrenocorticotropic hormone (ACTH; corticotropin) have been demonstrated by many investigators within the past year. These beneficial effects may be produced especially on rheumatoid arthritis and acute rheumatic fever but also on several other articular conditions such as the acute arthritis of gout, the arthritis of disseminated lupus erythematosus, of psoriasis, of ulcerative colitis and to a limited extent on the arthritis of tuberculosis and in certain cases of primary osteoarthritis. In general the relief lasts only during the period of hormonal administration.GENERAL RESULTS IN RHEUMATOID ARTHRITIS Varying degrees of improvement have been obtained in practically all cases of active rheumatoid arthritis, rheumatoid spondylitis and Still's disease (juvenile rheumatoid arthritis) in which cortisone and pituitary adrenocorticotropic hormone have been used. Most patients, even those with severe but reversible disease, have promptly obtained decided relief. Other patients whose
Article
Prolactin (PRL) is a peptide hormone produced by the pituitary gland and diverse extrapituitary sites, which triggers activation of various signaling pathways after binding to its receptor (PRLr) resulting in the activation of specific genes associated with the pleiotropic activities of PLR. To date, various PRLr isoforms have been described, generated by post-transcriptional or post-translational processes. PRL has been associated with the modulation of a variety of actions in the immune response and inflammatory processes in several physiologic and pathologic conditions. However, PRL can have opposite effects, which might be regulated by interaction with the various isoforms of PRLR and PRL variants, as well as the cellular and molecular microenvironment influence.
Article
Lymphocyte recirculation through secondary lymphoid organs is essential for immunosurveillance and lymphocyte effector functions. Here, we show that signals through β2-adrenergic receptors (β2ARs) expressed on lymphocytes are involved in the control of lymphocyte dynamics by altering the responsiveness of chemoattractant receptors. Agonist stimulation of lymphocyte β2ARs inhibited egress of lymphocytes from lymph nodes (LNs) and rapidly produced lymphopenia in mice. Physiological inputs from adrenergic nerves contributed to retention of lymphocytes within LNs and homeostasis of their distribution among lymphoid tissues. β2ARs physically interacted with CCR7 and CXCR4, chemokine receptors promoting lymphocyte retention in LNs. Activation of β2ARs enhanced retention-promoting signals through CCR7 and CXCR4, and consequently inhibited lymphocyte egress from LNs. In models of T cell-mediated inflammatory diseases, β2AR-mediated signals inhibited LN egress of antigen-primed T cells and reduced their recruitment into peripheral tissues. Thus, this study reveals a novel mechanism for controlling lymphocyte trafficking and provides additional insights into immune regulation by the nervous system. © 2014 Nakai et al.
Article
Synaptic plasticity mechanisms, i.e. the sequence of events that underlies persistent changes in synaptic strength as a consequence of transient alteration in neuronal firing, are greatly influenced by the ‘chemical atmosphere’ of the synapses, that is to say by the presence of molecules at the synaptic cleft able to fine-tune the activity of other molecules more directly related to plasticity. One of those fine tuners is adenosine, known for a long time as an ubiquitous neuromodulator and metamodulator and recognized early as influencing synaptic plasticity. In this review we will refer to the mechanisms that adenosine can use to affect plasticity, emphasizing aspects of the neurobiology of adenosine relevant to its ability to control synaptic functioning.This article is part of a Special Issue entitled Brain and Memory.
Article
Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus.
Article
β2-Adrenergic receptors (β2-ARs) transduce the effects of (nor)epinephrine on a variety of cell types and act as key mediators of the body’s reaction to stress. β2-ARs are also expressed on immune cells and there is ample evidence for their role in immunomodulation. A key regulator of the immune response and a target for regulation by stress-induced signals is the transcription factor Nuclear Factor-kappaB (NF-κB). NF-κB shapes the course of both innate and adaptive immune responses and plays an important role in susceptibility to disease. In this review, we summarise the literature that has been accumulated in the past 20 years on adrenergic modulation of NF-κB function. We here focus on the molecular basis of the reported interactions and show that both physiological and pharmacological triggers of β2-ARs intersect with the NF-κB signalling cascade at different levels. Importantly, the action of β2-AR-derived signals on NF-κB activity appears to be highly cell type specific and gene selective, providing opportunities for the development of selective NF-κB modulators.
Article
Importance Longitudinal studies have linked the systemic inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) with the risk of developing heart disease and diabetes mellitus, which are common comorbidities for depression and psychosis. Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear.Objective To test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis.Design, Setting, and Participants The Avon Longitudinal Study of Parents and Children (ALSPAC)is a prospective general population birth cohort study based in Avon County, England. We have studied a subsample of approximately 4500 individuals from the cohort with data on childhood IL-6 and CRP levels and later psychiatric assessments.Measurement of Exposure Levels of IL-6 and CRP were measured in nonfasting blood samples obtained in participants at age 9 years.Main Outcomes and Measures Participants were assessed at age 18 years. Depression was measured using the Clinical Interview Schedule–Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ), thus allowing internal replication; psychotic experiences (PEs) and psychotic disorder were measured by a semistructured interview.Results After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55; 95% CI, 1.13-2.14). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81; 95% CI, 1.01-3.28; and adjusted OR, 2.40; 95% CI, 0.88-6.22, respectively). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner.Conclusions and Relevance Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia.
Article
The proinflammatory cytokine interleukin-1β (IL-1β) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release.The signaling pathway by which IL-1β exerts this function involves the blood-brain-barrier and induced central prostaglandin synthesis, but the identity of the blood-brain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1R1) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-1β. Following both intraperitoneal and intravenous administration of IL-1β, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cell positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1β is dependent on IL-1R1s on non-hematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved.
Article
Inflammation dysregulation in placenta is implicated in the pathogenesis of numerous pregnancy complications. Glucocorticoids (GCs), universally considered anti-inflammatory, can also exert pro-inflammatory actions under some conditions, whereas whether and how GCs promote placental inflammation has not been intensively investigated. In this study, we reported the opposing regulation of rat placental inflammation by synthetic GC dexamethasone (Dex). When Dex was subcutaneously injected 1 h post LPS intraperitoneal challenge, neutrophil infiltration as well as pro-inflammatory Il1b, Il6 and Tnfa expression in rat placenta were significantly reduced. In contrast, Dex pretreatment for 24 h potentiated rat placental pro-inflammatory response to LPS and delayed inflammation resolution, which involved MAPKs and NF-kappaB activation. Mechanically, Dex pretreatment promoted 5-lipoxygenase (ALOX5) activation and increased leukotriene B4 production whereas inhibited the anti-inflammatory and pro-resolving lipid mediator lipoxin A4 (LXA4) biosynthesis in rat placenta via downregulating ALOX15 and ALOX15B expression. Moreover, LXA4 supplementation dampened Dex-potentiated placental inflammation, as well as suppressed Dex-mediated ALOX5 activation in vivo and in vitro. Taken together, these findings suggest that GCs exposure could promote placental inflammation initiation and delay resolution via disrupting LXA4 biosynthesis.
Article
The interaction between the sympathetic nervous system and the immune system has been documented over the last several decades. In this review, the neuroanatomical, cellular, and molecular evidence for neuroimmune regulation in the maintenance of immune homeostasis will be discussed, as well as the potential impact of neuroimmune dysregulation in health and disease.