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Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130: 226-238

Laboratory of Nutrition and Integrative Neurobiology, NutriNeuro, INRA UMR 1286, University Victor Segalen Bordeaux 2, Bordeaux, France.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 02/2011; 130(2):226-38. DOI: 10.1016/j.pharmthera.2011.01.014
Source: PubMed

ABSTRACT

There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.

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Available from: Andrew H Miller, Dec 22, 2013
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    • "Immune-inducing molecules can activate brain signalling via a variety of neural, humoral and cellular mechanisms. For example, cytokines may enter into the brain parenchyma passively through the leaky regions in the blood brain barrier (BBB) such as the choroid plexus (CP), by using cytokine-specific transport molecules or by transmission of cytokine signals via afferent vagus nerve fibers (reviewed in (Capuron and Miller, 2011; Dantzer, 2009; Dantzer et al., 2008). Mature T lymphocytes are able to enter the CNS via several routes during conditions of stress and in disease states (Ransohoff et al., 2003). "
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    ABSTRACT: The inflammation theory of depression, proposed over 20 years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced ‘omics’ technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.
    Full-text · Article · Nov 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "So how does the immune system talk to the brain during infection and inflammation? To answer this question several excellent reviews have covered immune-to-brain communication pathways that seem to be implicated in these responses (Capuron and Miller, 2011; Dantzer et al., 2008; McCusker and Kelley, 2013; Quan, 2014). In this current review these immune-to-brain communication pathways will be briefly summarized and the role of inflammatory transcription factors in these pathways will be further discussed. "
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    ABSTRACT: The time course of the induction of enzymes responsible for the formation of prostaglandin E2 (PGE2) after an inflammatory insult, in relation to the concomitant febrile response, suggests that peripherally generated PGE2 is involved in the induction of the early phase of fever, while centrally produced PGE2 exerts pyrogenic capacities during the later stages of fever within the hypothalamic median preoptic nucleus (MnPO). The actions of peripherally derived PGE2 on the brain might occur at the level of the organum vasculosum laminae terminalis (OVLT), which lacks a tight blood-brain barrier and is implicated in fever, while the effects of PGE2 within the MnPO might interfere with glutamatergic neurotransmission within a recently characterized central efferent pathway for the activation of cold-defence reactions. Using the fura-2 ratio imaging technique we, therefore, measured changes of the intracellular Ca(2+) concentration in primary neuroglial microcultures of rat OVLT and MnPO stimulated with PGE2 and/or glutamate. In cultures from the OVLT, as opposed to those derived from the MnPO, substantial numbers of neurons (8% of 385), astrocytes (19% of 645) and microglial cells (28% of 43) directly responded to PGE2 with a transient increase of intracellular Ca(2+). The most pronounced effect of PGE2 on cells from MnPO microcultures was its modulatory influence on the strength of glutamate-induced Ca(2+) signals. In 72 out of 512 neurons and in 105 out of 715 astrocytes PGE2 significantly augmented glutamate-induced Ca(2+) signals. About 30% of these neurons were GABAergic. These observations are in agreement with putative roles of peripheral PGE2 as a directly acting circulating agent at the level of the OVLT, and of central MnPO-intrinsic PGE2 as an enhancer of glutamatergic neurotransmission, which causes disinhibition of thermogenic heat production, a crucial component for the manifestation of fever. In microcultures from both brain sites investigated incubation with PGE2 significantly reduced the lipopolysaccharide-induced release of cytokines (tumor necrosis factor-α and interleukin-6) into the supernatant. PGE2, thus, seems to be involved in a negative feed-back loop to limit the strength of the brain inflammatory process and to play a dual role with pro- as well as anti-inflammatory properties.
    Full-text · Article · Nov 2015 · Neuroscience
    • "So how does the immune system talk to the brain during infection and inflammation? To answer this question several excellent reviews have covered immune-to-brain communication pathways that seem to be implicated in these responses (Capuron and Miller, 2011; Dantzer et al., 2008; McCusker and Kelley, 2013; Quan, 2014). In this current review these immune-to-brain communication pathways will be briefly summarized and the role of inflammatory transcription factors in these pathways will be further discussed. "
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    ABSTRACT: Immune-to-brain communication pathways involve humoral mediators, including cytokines, central modulation by neuronal afferents and immune cell trafficking to the brain. During systemic inflammation these pathways contribute to mediating brain-controlled sickness symptoms including fever. Experimentally, activation of these signaling pathways can be mimicked and studied when injecting animals with pathogen associated molecular patterns (PAMPS). One central component of the brain inflammatory response, which leads, for example, to fever induction, is transcriptional activation of brain cells via cytokines and PAMPS. We and others have studied the spatiotemporal activation and the physiological significance of transcription factors for the induction of inflammation within the brain and the manifestation of fever. Evidence has revealed a role of nuclear factor (NF)κB in the initiation, signal transducer and activator of transcription (STAT)3 in the maintenance and NF-interleukin (IL)6 in the maintenance or even termination of brain-inflammation and fever. Moreover, psychological stressors, such as exposure to a novel environment, leads to increased body core temperature and genomic NF-IL6-activation, suggesting a potential use of NF-IL6-immunohistochemistry as a multimodal brain cell activation marker and a role for NF-IL6 for differential brain activity. In addition, the nutritional status, as reflected by circulating levels of the cytokine-like hormone leptin, influence immune-to-brain communication and age-dependent changes in LPS-induced fever. Overall, transcription factors remain therapeutically important targets for the treatment of brain-inflammation and fever induction during infectious / non-infectious inflammatory and psychological stress. However, the exact physiological role and significance of these transcription factors requires to be further investigated.
    No preview · Article · Sep 2015 · Brain Behavior and Immunity
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