Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice

Nguyen, Kimchi; D’Mello, Charlotte; Le, Tai; Urbanski, Stefan J.; Swain, Mark G.

doi:10.1016/j.jhep.2011.09.014

Cited by 31 publications

(24 citation statements)

References 51 publications

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“…Previous studies in IL-6 knockout mice and in wild type mice injected with sgp130 suggest IL-6 trans -signaling has a role in behavioral changes caused by peripheral infection (Burton et al, 2011; Nguyen et al, 2011). Another study involving aged mice suggested that increased IL-6 trans -signaling inhibits consolidation of memories that are hippocampal dependent (Burton and Johnson, 2011).…”

Section: Resultsmentioning

confidence: 98%

Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice

Burton

Rytych

Freund

et al. 2013

Brain, Behavior, and Immunity

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During systemic infection, inflammatory cytokines such as interleukin (IL)-6 are produced in excess in the brain of aged mice and induce severe behavioral deficits. However, no studies have examined how pro-inflammatory IL-6 trans-signaling is involved in the exaggerated production of IL-6 in the aged brain, nor the extent to which IL-6 trans-signaling affects other markers of neuroinflammation, adhesion molecules, and behavior. Therefore, this study investigated in aged mice the presence of IL-6 signaling subunits in microglia; the central effects of soluble gp130 (sgp130)—a natural inhibitor of the IL-6 trans-signaling pathway—on IL-6 production in microglia; and the effects of sgp130 given intracerebroventricularly (ICV) on neuroinflammation and sickness behavior caused by i.p. injection of lipopolysaccharide (LPS). Here we show that microglia isolated from aged mice have higher expression of IL-6 receptor (IL-6R) compared to microglia from adults; and the level of mRNA for ADAM17, the enzyme responsible for shedding membrane-bound IL-6R in trans-signaling, is higher in the hippocampus of aged mice compared to adults. Additionally, we show in aged mice that peripheral LPS challenge elicits a hyperactive IL-6 response in microglia, and selective blockade of trans-signaling by ICV injection of sgp130 mitigates this. The sgp130-associated inhibition of IL-6 was paralleled by amelioration of exaggerated and protracted sickness behavior in aged mice. Taken together, the results show that microglia are important regulators of the IL-6 trans-signaling response in the aged brain and sgp130 exerts an anti-inflammatory effect by inhibiting the pro-inflammatory arm of IL-6 signaling.

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Section: Resultsmentioning

confidence: 98%

Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice

Burton

Rytych

Freund

et al. 2013

Brain, Behavior, and Immunity

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“…It has been suggested that IL-6 play a critical role in mediating sickness behaviour in mice with liver inflammation. In this model, sickness behaviour is associated with cerebral endothelial cell activation as well as higher levels of IL-6 in the liver and peripheral circulation, all of which are significantly reduced in IL-6 deficient mice (Nguyen et al 2012). Together, these findings suggest that alterations in the integrity of the BBB and/or the blood-CSF barrier (Muller et al 1999; Schwarz et al 1998), in the form of increased transmigration of inflammatory cells into the brain due to activation of endothelial cells in cerebral vasculature, play a crucial role in the peripheral immune-to-brain communication.…”

Section: Schizophrenia Is Associated With Alteration In Components Ofmentioning

confidence: 99%

Is there a role for immune-to-brain communication in schizophrenia?

2015

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Schizophrenia is characterised by hallucinations, delusions, depression-like so-called negative symptoms, cognitive dysfunction, impaired neurodevelopment and neurodegeneration. Epidemiological and genetic studies strongly indicate a role of inflammation and immunity in the pathogenesis of symptoms of schizophrenia. Evidence accrued over the last two decades has demonstrated that there are a number of pathways through which systemic inflammation can exert profound influence on the brain leading to changes in mood, cognition and behaviour. The peripheral immune system-to-brain communication pathways have been studied extensively in the context of depression where inflammatory cytokines are thought to play a key role. In this review, we highlight novel evidence suggesting an important role of peripheral immune-to-brain communication pathways in schizophrenia. We discuss recent population-based longitudinal studies that report an association between elevated levels of circulating inflammatory cytokines and subsequent risk of psychosis. We discuss emerging evidence indicating potentially important role of blood–brain barrier endothelial cells in peripheral immune-to-brain communication, which may be also relevant for schizophrenia. Drawing on clinical and preclinical studies, we discuss whether immune-mediated mechanisms could help to explain some of the clinical and pathophysiological features of schizophrenia. We discuss implication of these findings for approaches to diagnosis, treatment and research in future. Finally, pointing towards links with early-life adversity, we consider whether persistent low-grade activation of the innate immune response, as a result of impaired foetal or childhood development, could be a common mechanism underlying the high comorbidity between certain neuropsychiatric and physical illnesses, such as schizophrenia, depression, heart disease and type-two diabetes.

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“…They are able to control the production of pro-inflammatory cytokines by activated immune cells during peripheral inflammation, and are being investigated clinically as potential therapeutic agents for the treatment of numerous immune-mediated diseases (4). Studies on Tregs in human autoimmunity have primarily focused on peripheral blood samples.…”

Section: Introductionmentioning

confidence: 99%

BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

Zhang

et al. 2013

Braz J Med Biol Res

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Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

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Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice

Cited by 31 publications

References 51 publications

Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice

Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice

Is there a role for immune-to-brain communication in schizophrenia?

BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

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