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Gut reaction to IL-17
Whether IL-17A/F or TH17 cells are necessary for the immunopathogenesis of human multiple sclerosis (MS) has been a topic of active debate. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, in mice deficient for IL-17A and IL-17F, Regen et al. found that IL-17 ablation reduced susceptibility to EAE. However, adoptive transfer of TH17 cells from autoantigen-primed IL-17–deficient mice recapitulated disease in naïve control mice but not in IL-17–deficient mice. Cohousing IL-17–deficient mice with IL-17–expressing mice, fecal transplantation from IL-17–expressing mice into IL-17–deficient mice, and reexpression of IL-17A in the gut of IL-17–deficient mice restored susceptibility to EAE. Thus, IL-17 expression in the gut rather than its effector function in the CNS is directly linked to EAE susceptibility by modulating the gut microbiome.
Abstract
Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type–like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F–deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
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