FIGURE 1 - uploaded by Diana Casper
Content may be subject to copyright.
Autonomic control of splenic macrophages can modulate systemic inflammation after injury 

Autonomic control of splenic macrophages can modulate systemic inflammation after injury 

Source publication
Article
Full-text available
Recent evidence suggests a link between brain injury and the autonomic release of pro-inflammatory cytokines by resident macrophages in the spleen. This phenomenon, termed "brain-spleen inflammatory coupling," has garnered attention from scientific and medical communities interested in developing novel treatments for traumatic brain injury (TBI). C...

Context in source publication

Context 1
... within the peritoneal cavity, the spleen monitors the circulation and removes foreign material in the blood that potentially threatens homeostasis. As the primary mediator of the mononuclear phagocyte system, splenic leukocytes in the red and white pulp prevent devastating infections by encapsulated bacteria and intracellular pathogens. It comes as a surprise, then, that the same organ that plays such a crucial role in preventing infection may simultaneously exacerbate the inflammatory response after brain injury. With this in mind, a fresh body of evidence has suggested a link between brain injury and the autonomic release of inflammatory cytokines by macrophages in the spleen ( Figure 1). This phenomenon, termed “brain-spleen inflammatory coupling,” has garnered attention from scientific and medical communities seeking new treatments for ischemic and traumatic brain injuries. Physicians and scientists readily acknowledge that the intricate mechanisms driving acute inflammation remain a mystery. Dr. Niels Jerne, a Nobel Prize–winning immunologist, once described the immune system as a network of interacting cells and antibodies, analogous to the communication among neurons, glia, and their neurotransmitters in the central nervous system (CNS) (Jerne, 1985). For decades, these systems were thought to function independently; however, scientists have discovered several physiologic processes linking them. In the 1980s, Damjanovich and colleagues discovered that lymphocytes possess excitable membranes that behave similarly to those of neurons (Damjanovich et al., 1989). Leukocytes have also been shown to express β 2-adrenergic receptors, indicating they are sensitive to changes in autonomic output (Bruynzeel, 1984). These findings provided the framework for the development of theories describing neurotransmitter control of inflammation and the link between emotional states and immune status. In a broad sense, inflammation is a paradox of complexity. For example, the CNS was once considered an “immune privileged” site due to the lack of sentinel lymphocytes in the brain (Medawar, 1948; Barker and Billingham, 1977; Prendergast and Anderton, 2009) and the apparent lack of cellular transport and selective molecular permeability through the blood- brain barrier. While this property holds true under normal physiologic conditions, acute injuries to the brain ignite a strong inflammatory response by endogenous neurons, astrocytes, and microglia. In addition, circulating lymphocytes and macrophages are found within the brain parenchyma even in the absence of damage to the blood-brain barrier (Dickson et al., 1993). Outside the brain, the systemic inflammatory response is often a normal reactive process driven by a vast array of cytokines, chemokines, stress hormones, and stereotypical cellular and vascular responses. However, when inflammation is left unchecked, it can be more deleterious than the primary injury itself. Immune cells must allow the body to respond properly to injury, but at the same time prevent collateral damage to uninjured cells. This dichotomy is exemplified in the CNS, where a robust inflammatory response is mounted after ischemic and traumatic injury. Unfortunately, this often leads to significant neuronal death and edema, which can be fatal. While the primary and immediate consequences of mechanical trauma to neurons cannot be undone, secondary pathological sequelae, specifically brain swelling and inflammation, are considered targets for therapeutic intervention. Proponents of the brain-spleen inflammatory coupling hypothesis point to the physiologic phenomenon of post-traumatic changes in autonomic output as the main mechanism driving the coupling (Borovikova et al., 2000; Tracey, 2002). Immediately after injury, damaged neurons and surrounding glia release locally acting, pro-inflammatory cytokines, which stimulate the posterior hypothalamus to increase systemic sympathetic output. This leads to numerous hormonal and systemic responses such as catecholamine release from the adrenal medulla, peripheral vasoconstriction, and positive chrono- and ionotropic stimulation of the heart. The cumulative effects of these changes contribute to the “fight-or-flight” response. Several authors have demonstrated that resident macrophages in the spleen and liver also express adrenergic/cholinergic receptors and are therefore sensitive to changes in autonomic output (Wang et al., 2003; Ajmo et al., 2009; Rosas-Ballina and Tracey, 2009). After acute brain injury, splenic macrophages are adrenergically stimulated to secrete massive amounts of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF- α ) and interleukin-1 beta (IL- 1 β ) into the peripheral circulation (Tracey, 2002). These inflammatory cytokines eventually reach and penetrate the disrupted blood-brain barrier and enhance the post-traumatic immunologic response. Increased sympathetic tone leads to the release of pro-inflammatory cytokines and, conversely, this predicts that increased parasympathetic tone, or cholinergic stimulation, would be anti-inflammatory, perhaps by its effects on splenic macrophages (Vida et al., 2011). In 2000, Borovikova and colleagues demonstrated that direct electrical stimulation of the vagus nerve lowered the concentration of TNF- α in serum and prevented the progression of septic shock in rats during lethal endotoxemia (Borovikova et al., 2000). This was the first study to propose a pathway for CNS regulation of the immune response, or a “cholinergic anti-inflammatory pathway.” In 2002, Wang and colleagues determined that the nicotinic acetylcholine receptor α 7 subunit ( α ...

Citations

... Brain-spleen inflammatory coupling, a crosstalk between brain injury and the autonomic release of peripheral cytokines by resident macrophages in the spleen, is evidenced in a traumatic brain injury model (Rasouli, Lekhraj, Ozbalik, Lalezari, & Casper, 2011). Inflammatory cytokines associated with splenic dysfunction were significantly increased in the plasma of APP/PS1/Tau transgenic mouse (Yang, Kim, Lee, & Kim, 2015). ...
Article
Pseudostellaria heterophylla, has historically been used as medicine food homology plant for thousand years in China. Our previous studies had indicated that daily intake of Pseudostellaria heterophylla extract enhanced cognitive memory. Herein, heterophyllin B (HET-B), a brain permeable cyclopeptide from Pseudostellaria heterophylla was determined, and the molecular mechanism underlying its memory improvement effects was investigated. Pseudostellaria heterophylla extract as well as HET-B reversed Aβ25-35-induced axonal atrophy and neuronal apoptosis in cultured cortical neurons of mice. HET-B could enhance memory retrieval, modulate splenic T helper cell, and ameliorate neuroinflammation in i.c.v. Aβ1-42 injected Alzheimer’s disease (AD) mice. To explore the mechanism of action, network pharmacology was performed to predict protein targets and pathways of HET-B against AD. Five key targets were identified related to the effect of HET-B in AD intervention, and were clarified involved in axonal regeneration. We revealed for the first time that HET-B promoted memory retrieval through axonal regeneration and anti-neuroinflammation. This study provides a basis to research on HET-B as nutritional supplements for brain healthy.
... Similar to stroke, the role of the spleen has been reported in the progression of many other devastating disease conditions such as MI (3) , SCI (4) , TBI (101) , sepsis (12) as well as SARS-CoV-2 (5) . In many of these conditions, the splenic activation is mediated by the SNS and release of noradrenaline (e.g NE) that activate the β-ARs present on the splenic lymphocytes and macrophages (102)(103)(104)(105)(106)(107) . ...
Article
Modulation of peripheral immune cells in the spleen plays a key role in many life-threatening conditions such as stroke. Immune cell changes can lead to the excessive release of pro-inflammatory cytokines into the circulation and preferential loss of innate immune cells which can further exacerbate tissue damage and predispose patients to infectious complications. Reversing these processes represents an attractive treatment strategy and has shown to have beneficial effects in animal models of ischemic stroke, sepsis, traumatic brain injury (TBI) as well as myocardial infraction (MI). However, systemic interventions are often challenging to deliver due to the non-selective broad range of action of many treatments. More selective targeted treatment approaches are therefore desirable. The spleen is considered a natural filtration site for many nanomaterials due to the spontaneous tendency of this organ to filter blood-borne molecules. This selective targeting of nanomaterials to the spleen therefore offers considerable potential in the management of many conditions affected by peripheral inflammation. In this review, we will explore the key nanomaterials-related parameters that mediate splenic targeting and how these could influence the actual localization and function of nanomaterials once in the spleen. We aim to emphasize the potential of utilising nanomaterials as selective tools for peripheral immunomodulation to accelerate clinical translation.
... Microglia in aged mice showed impairments in phagocytic activity and higher IL-1β production. Deficits of phagocytosis were observed in myeloid of inflammatory cytokines of the surrounding glia stimulates the posterior hypothalamus to increase norepinephrine production after neurological injury (Al-Sadi et al., 2014;Rasouli et al., 2011;Royes and Gomez-Pinilla, 2019;Tracey, 2002). Increased sympathetic activity post-TBI also leads to splanchnic hypoperfusion and aberrant intestinal permeability, which are evidenced as an elevated ratio of orally ingested lactulose (a marker of paracellular permeability) to mannitol (a marker of transcellular permeability) in the urine of TBI patients (McHugh et al., 2007). ...
Article
Traumatic brain injury (TBI) is a non-degenerative and non-congenital insult to the brain and is recognized as a global public health problem, with a high incidence of neurological disorders. Despite the causal relationship not being entirely known, it has been suggested that multiorgan inflammatory response involving the autonomic nervous system and the spleen-gut brain axis dysfunction exacerbate the TBI pathogenesis in the brain. Thus, applying new therapeutic tools, such as physical exercise, have been described in the literature to act on the immune modulation induced by brain injuries. However, there are caveats to consider when interpreting the effects of physical exercise on this neurological injury. Given the above, this review will highlight the main findings of the literature involving peripheral immune responses in TBI-induced neurological damage and how changes in the cellular metabolism of the spleen-gut brain axis elicited by different protocols of physical exercise alter the pathophysiology induced by this neurological injury.
... Brainspleen inflammatory coupling is phenomena that indicate the important connection of immune activity of spleen and brain function. In brain injury, the production of spleen cytokines increases dramatically and results in brain inflammation (22). In addition, spleen production such as Syk (spleen tyrosine kinase) has been reported to have a regulatory effect in (AD). ...
Article
Full-text available
Molecular study of garlic as a popular food ingredient could better understand its health benefits such as immunological effects. For this aim, effects of garlic on the spleen and possible side effects including oxidative stress increment, the molecular mechanism is investigated through network analysis of differentially expressed genes in the treatment of garlic. Protein-protein interaction (PPI) network analysis of spleen gene expression profile of Mus musculus (8-week old male C57BL/6J mice) in garlic treatments from a microarray study with the code of GSE10344 was analyzed via GEO2R software. Furthermore, Cytoscape V 3.7.1 was applied to construct and analyze a network of up- and down-regulated genes. The differentially expressed genes (DEGs) were analyzed via the CluePedia plugin of Cytoscape to determine expression patterns. After the identification of central nodes, an action map was created. A total of 77 DEGs were achieved which were including 40 up-regulated and 37 Down-regulated. The centrality analysis of the network indicated that Vcan, Lamb1, and Ltbp1 are hubs and Glra1, Wdr17, Nefl, and Becn1 are bottlenecks. Mutual regulatory connections between hubs and Alb and App (as two non-queried hubs) were determined. The findings indicate that garlic effect on the spleen and its mechanism may be involved mostly with App dysregulation.
... Furthermore, this study examined splenic immune response, a reservoir for peripheral immune cells, to determine whether changes in monocytes and neutrophils in the periphery associated with outcomes in the brain. Neutrophils in the blood were higher in male TBI mice than male shams at 7DPI, and the spleen sequesters immune cells chronically and will show brain injury effects longer than circulating blood (Rasouli, Lekhraj, Ozbalik, Lalezari, & Casper, 2011). As expected, male TBI mice had higher neutrophil population percentages compared with female TBI mice. ...
Article
Full-text available
Identifying differential responses between sexes following traumatic brain injury (TBI) can elucidate the mechanisms behind disease pathology. Peripheral and central inflammation in the pathophysiology of TBI can increase sleep in male rodents, but this remains untested in females. We hypothesized that diffuse TBI would increase inflammation and sleep in males more so than in females. Diffuse TBI was induced in C57BL/6J mice and serial blood samples were collected (baseline, 1, 5, 7 days post‐injury [DPI]) to quantify peripheral immune cell populations and sleep regulatory cytokines. Brains and spleens were harvested at 7DPI to quantify central and peripheral immune cells, respectively. Mixed effects regression models were used for data analysis. Female TBI mice had 77–124% higher IL‐6 levels than male TBI mice at 1 and 5DPI, whereas IL‐1β and TNF‐α levels were similar between sexes at all timepoints. Despite baseline sex differences in blood‐measured Ly6Chigh monocytes (females had 40% more than males), TBI reduced monocytes by 67% in TBI mice at 1DPI. Male TBI mice had 31‐33% more blood‐measured and 31% more spleen‐measured Ly6G+ neutrophils than female TBI mice at 1 and 5DPI, and 7DPI, respectively. Compared with sham, TBI increased sleep in both sexes during the first light and dark cycles. Male TBI mice slept 11–17% more than female TBI mice, depending on the cycle. Thus, sex and TBI interactions may alter the peripheral inflammation profile and sleep patterns, which might explain discrepancies in disease progression based on sex.
... Apart from the blood, peripheral lymphoid organs such as the spleen may also reflect brain inflammation. The spleen plays a central role in recruiting and priming immune cells and recent evidence suggests a link between brain injury and the release of pro-inflammatory cytokines by resident macrophages in the spleen (17). Increased levels of cytokines have also been reported in activated rat splenocytes following epileptic seizures (18). ...
... The spleen receives a rich supply of sympathetic innervation, and has lately gained attention for its pivotal role in modulating the immune response (58). The phenomenon is sometimes referred to as brainspleen inflammatory coupling (17). Experimental studies have described dense innervation of spleen tissue with receptors on macrophages and/or lymphocytes that in turn modulate the immune response (59)(60)(61)(62). ...
Article
Full-text available
Non-convulsive status epilepticus (NCSE) is a prolonged epileptic seizure with subtle symptoms that may delay clinical diagnosis. Emerging experimental evidence shows brain pathology and epilepsy development following NCSE. New diagnostic/prognostic tools are therefore needed for earlier and better stratification of treatment. Here we examined whether NCSE initiates a peripheral immune response in blood serum from rats that experienced electrically-induced NCSE. ELISA analysis showed an acute transient increase in serum protein levels including interleukin-6 6 h post-NCSE, similar to the immune reaction in the brain. At 4 weeks post-NCSE, when 75% of rats subjected to NCSE had also developed spontaneous seizures, several immune proteins were altered. In particular, markers associated with microglia, macrophages and antigen presenting cells, such as CD68, MHCII, and galectin-3, were increased and the T-cell marker CD4 was decreased in serum compared to both non-stimulated controls and NCSE rats without spontaneous seizures, without correlation to interictal epileptiform activity. Analyses of serum following intracerebral injection of lipopolysaccharide (LPS) showed an acute increase in interleukin-6, but at 4 weeks unaltered levels of MHCII and galectin-3, an increase in CD8 and CD11b and a decrease in CD68. None of the increased serum protein levels after NCSE or LPS could be confirmed in spleen tissue. Our data identifies the possibility to detect peripheral changes in serum protein levels following NCSE, which may be related to the development of subsequent spontaneous seizures.
... This phenomenon known as brain spleen inflammatory coupling. Again spleen is a major marker of inflammation [50]. So to access inflammatory state of central nervous system and to correlate with haematological changes, histology of spleen was taken into account. ...
Article
Full-text available
Objective: To evaluate the anti-hyperprolactinemic effect of methanolic extract of Tinospora cordifolia against antipsychotic/neuroleptic drug induced hyperprolactinemia. Methods: A total of 48 Wistar albino rats were chosen in the study. To induce hyperprolactinemia, haloperidol at 5 mg/kg/day was intraperitoneally administered for 16 continuous days and sulpiride at 20 mg/kg/day was administered intraperitoneally for 28 continuous days. Methanolic extract of Tinospora cordifolia at 200 mg/kg/day and 400 mg/kg/day were administered orally 30 min before administration of haloperidol and sulpiride for 16 and 28 days, respectively. Then, we had evaluated prolactin, dopamine and antioxidant status in the treatment group as compared to haloperidol and sulpiride. Results: There was a significant (P<0.05) increase in serum prolactin level and decrease in dopamine level in the haloperidol and sulpiride treated animals. However, methanolic extract of Tinospora cordifolia significantly (P<0.05) decreased serum prolactin level and increased brain dopamine level. Further, superoxide dismutase and catalase level were also decreased significantly in the haloperidol and sulpiride treated groups as compared to those of the control group and the antioxidant status was restored significantly on treatment with methanolic extract of Tinospora cordifolia. Furthermore, methanolic extract of Tinospora cordifolia also reduced total leukocyte count, and increased red blood cell count and hemoglobin concentration. In addition, the spleen did not show signs of infection or inflammation in the experiments. Conclusions: Methanolic extract of Tinospora cordifolia has a significant antihyperprolactinemic effect which may be attributed to neuroprotective and antioxidant effects of its signature constituents like stepharanine.
... Splenic activation is associated with altered inflammatory responses, immune system dysregulation, neuroinflammation, increased infection risk and impaired neurological recovery. 12,13 Pre-clinical studies showed that the spleen acutely decreases in size and changes its cellular composition upon ischemic stroke onset and the degree of splenic contraction positively correlated with stroke volume. 14,15 Obliteration of splenic response pre-or post-stroke either by removing or radiating the spleen reduces infarct size and enhanced recovery in experimental ischemic stroke models. ...
Article
Growing evidences suggest that stroke is a systemic disease affecting many organ systems beyond the brain. Stroke-related systemic inflammatory response and immune dysregulations may play an important role in brain injury, recovery, and stroke outcome. The two main phenomena in stroke-related peripheral immune dysregulations are systemic inflammation and post-stroke immunosuppression. There is emerging evidence suggesting that the spleen contracts following ischemic stroke, activates peripheral immune response and this may further potentiate brain injury. Whether similar brain–immune crosstalk occurs in hemorrhagic strokes such as intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) is not established. In this review, we systematically examined animal and human evidence to date on peripheral immune responses associated with hemorrhagic strokes. Specifically, we reviewed the impact of clinical systemic inflammatory response syndrome (SIRS), inflammation- and immune-associated biomarkers, the brain–spleen interaction, and cellular mediators of peripheral immune responses to ICH and SAH including regulatory T cells (Tregs). While there is growing data suggesting that peripheral immune dysregulation following hemorrhagic strokes may be important in brain injury pathogenesis and outcome, details of this brain-immune system cross-talk remain insufficiently understood. This is an important unmet scientific need that may lead to novel therapeutic strategies in this highly morbid condition.
... 5 The release of locally acting proinflammatory cytokines from damaged neurons and surrounding glia stimulate the posterior hypothalamus to increase systemic sympathetic output, including catecholamine release from the adrenal medulla into the bloodstream. 6 In relation to its role in immune responses, 7 the spleen is an important target for studying the peripheral markers of AD. Activation of adrenergic and cholinergic receptors, expressed on splenic macrophages, regulates the secretion of proinflammatory cytokines into the peripheral circulation, which pass the blood-brain barrier and enhance the immunologic response. ...
Article
Full-text available
Pathologic inflammation in response to injury, infection, or oxidative stress is a proposed mechanism relating cognitive decline to dementia. The kynurenine pathway and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators, TXNIP, and oxidative damage in the cerebrum and spleen, including inflammatory cytokine production by stimulated splenocytes, from female triple transgenic (3xTg-AD) mice in early and late stages of disease progression, and characterized tissue-specific epigenetic regulation of Txnip gene expression. We show that cognitive deficits in 7-month-old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen tryptophan metabolites, with a concomitant increase in amyloid β 40 (Aβ40)/Aβ42 and tau/hyperphosphorylated tau pathologies and a coordinated reduction in spleen proinflammatory cytokine production in 17-month-old mice. The enhanced cerebrum TXNIP expression is associated with increased histone acetylation, transcription factor [Aβ42 or CCCTC-binding factor (CTCF)] binding, and Txnip promoter hypomethylation, whereas the attenuated spleen TXNIP expression is associated with increased histone methylation, reduced CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan metabolism, inflammatory cytokine production, and cognitive decline; and they provide a potential mechanism for Txnip gene regulation in normal and pathologic conditions, suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aβ40/Aβ42 targeted AD therapies.
... Stimulation of α/β-AR located on splenic macrophages leads to the release of TNF-α and IL-1β, which enhance and exacerbate inflammation. Conversely, parasympathetic stimulation of α7nAChR inhibits the release of these cytokines, thereby attenuating the inflammatory response to injury [176]. ...
Article
Full-text available
Stroke is the most common cerebrovascular disease, the second leading cause of death behind heart disease and is a major cause of long-term disability worldwide. Currently, systemic immunomodulatory therapy based on intravenous cells is attracting attention. The immune response to acute stroke is a major factor in cerebral ischaemia (CI) pathobiology and outcomes. Over the past decade, the significant contribution of the spleen to ischaemic stroke has gained considerable attention in stroke research. The changes in the spleen after stroke are mainly reflected in morphology, immune cells and cytokines, and these changes are closely related to the stroke outcomes. Autonomic nervous system (ANS) activation, release of central nervous system (CNS) antigens and chemokine/chemokine receptor interactions have been documented to be essential for efficient brain-spleen cross-talk after stroke. In various experimental models, human umbilical cord blood cells (hUCBs), haematopoietic stem cells (HSCs), bone marrow stem cells (BMSCs), human amnion epithelial cells (hAECs), neural stem cells (NSCs) and multipotent adult progenitor cells (MAPCs) have been shown to reduce the neurological damage caused by stroke. The different effects of these cell types on the interleukin (IL)-10, interferon (IFN), and cholinergic anti-inflammatory pathways in the spleen after stroke may promote the development of new cell therapy targets and strategies. The spleen will become a potential target of various stem cell therapies for stroke represented by MAPC treatment.