Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells

Benakis, Corinne; Brea, David; Caballero, Silvia; Faraco, Giuseppe; Moore, Jamie; Murphy, Michelle; Sita, Giulia; Racchumi, Gianfranco; Ling, Lilan; Pamer, Eric G.; Iadecola, Costantino; Anrather, Josef

doi:10.1038/nm.4068

Cited by 830 publications

(930 citation statements)

References 62 publications

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“…Moreover, changing microbiota composition unmasks a heretofore unknown suppression of the trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis (Benakis et al, 2016).…”

Section: Microbiota and Strokementioning

confidence: 99%

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

Dinan

Cryan

2016

Neuropsychopharmacol

191

121

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There is now a large volume of evidence to support the view that the immune system is a key communication pathway between the gut and brain, which plays an important role in stress-related psychopathologies and thus provides a potentially fruitful target for psychotropic intervention. The gut microbiota is a complex ecosystem with a diverse range of organisms and a sophisticated genomic structure. Bacteria within the gut are estimated to weigh in excess of 1 kg in the adult human and the microbes within not only produce antimicrobial peptides, short chain fatty acids, and vitamins, but also most of the common neurotransmitters found in the human brain. That the microbial content of the gut plays a key role in immune development is now beyond doubt. Early disruption of the host-microbe interplay can have lifelong consequences, not just in terms of intestinal function but in distal organs including the brain. It is clear that the immune system and nervous system are in continuous communication in order to maintain a state of homeostasis. Significant gaps in knowledge remain about the effect of the gut microbiota in coordinating the immune-nervous systems dialogue. However, studies using germ-free animals, infective models, prebiotics, probiotics, and antibiotics have increased our understanding of the interplay. Early life stress can have a lifelong impact on the microbial content of the intestine and permanently alter immune functioning. That early life stress can also impact adult psychopathology has long been appreciated in psychiatry. The challenge now is to fully decipher the molecular mechanisms that link the gut microbiota, immune, and central nervous systems in a network of communication that impacts behavior patterns and psychopathology, to eventually translate these findings to the human situation both in health and disease. Even at this juncture, there is evidence to pinpoint key sites of communication where gut microbial interventions either with drugs or diet or perhaps fecal microbiota transplantation may positively impact mental health.

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Section: Microbiota and Strokementioning

confidence: 99%

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

Dinan

Cryan

2016

Neuropsychopharmacol

191

121

View full text Add to dashboard Cite

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“…9 Although several studies suggest detrimental functions of IL-17-producing γδ T cells in stroke, their exact phenotype is unclear. 5,10,11 In this study, we classified γδ T cells in detail, studied the role of the chemokine receptor CCR6 for their migration, and investigated their effects on stroke outcome. To further explore the therapeutic potential of an IL-17 neutralization, we combined the treatment with anti-IL-17 antibodies with mild therapeutic hypothermia (TH).…”

Section: Strokementioning

confidence: 99%

CCR6 (CC Chemokine Receptor 6) Is Essential for the Migration of Detrimental Natural Interleukin-17–Producing γδ T Cells in Stroke

Arunachalam

Ludewig

Melich

et al. 2017

Stroke

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S troke is worldwide ranked as the second most common cause of death and the third most common cause of disability-adjusted life years.1 Numerous experimental and clinical studies demonstrate that the activation of the systemic immune compartment and brain resident immune cells is a major element of the pathophysiology of stroke. Recently, clinical studies targeting T cells highlighted the therapeutic potential of immune modulatory treatment strategies. T-cell-related detrimental mechanisms in cerebral ischemia encompass perforin-mediated neurotoxicity and the production of the proinflammatory cytokines interleukin-17 (IL-17) and IL-21.3-5 Whereas IL-21 and perforin are thought to be directly neurotoxic, IL-17 effects mainly depend on the induction of proinflammatory chemokines, which are leading to a rapid neutrophil infiltration into ischemic hemispheres. Major sources of IL-17 in ischemic brains are γδ T cells, which are producing IL-17 within 24 hours after the ischemic attack. 5 The temporal dynamics of the IL-17 production in γδ T cells indicate that antigen-specific priming is not essential for their activation. 5,6 In models of acute infection, similarly rapid IL-17 responses are mounted by γδ T cells before the antigen-specific activation of T cells and B cells. IL-17-producing γδ T cells can be divided into several subsets. So-called natural IL-17-producing γδ T cells (nTγδ17 cells) are producing IL-17 within 12 hours. 8 The rapid antigen-independent activation of nTγδ17 cells can occur through Background and Purpose-Immune-mediated tissue damage after stroke evolves within the first days, and lymphocytes contribute to the secondary injury. Our goal was to identify T-cell subpopulations, which trigger the immune response. Methods-In a model of experimental stroke, we analyzed the immune phenotype of interleukin-17 (IL-17)-producing γδ T cells and explored the therapeutic potential of neutralizing anti-IL-17 antibodies in combination with mild therapeutic hypothermia. Results-We show that brain-infiltrating IL-17-positive γδ T cells expressed the Vγ6 segment of the γδ T cells receptor and were largely positive for the chemokine receptor CCR6 (CC chemokine receptor 6), which is a characteristic for natural IL-17-producing γδ T cells. These innate lymphocytes are established as major initial IL-17 producers in acute infections. Genetic deficiency in Ccr6 was associated with diminished infiltration of natural IL-17-producing γδ T cells and a significantly improved neurological outcome. In the ischemic brain, IL-17 together with tumor necrosis factor-α triggered the expression of CXC chemokines and neutrophil infiltration. Therapeutic targeting of synergistic IL-17 and tumor necrosis factor-α pathways by IL-17 neutralization and therapeutic hypothermia resulted in additional protective effects in comparison to an anti-IL-17 antibody treatment or therapeutic hypothermia alone. Conclusions-Brain-infiltrating IL-17-producing γδ T cells belong to the subset of natural IL-17-producing γδ T cells. In stroke, th...

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“…The interaction between the central nervous system (CNS) and the immune system is complex as shown by the recent observation that Treg cells in the gut regulate the infiltration of γδ T cells in the ischemic mouse brain tissue [37]. This crosstalk could be an adaptive response to dampen brain damage and limit harmful immune responses to brain-derived antigens.…”

Section: Introductionmentioning

confidence: 99%