Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis

Abstract

Innate immune mechanisms essential for priming encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a IL-17-producing Th (Th17) cell-mediated autoimmune disease and an animal model of multiple sclerosis. To investigate how upstream TLR signals influence autoimmune T cell responses, we studied the role of individual TLR and MyD88, the common TLR adaptor molecule, in the initiation of innate and adaptive immune responses in EAE. Wild type (WT) C57BL/6, TLR-deficient and MyD88-deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) in CFA. MyD88 -/-mice were completely EAE resistant. Purified splenic myeloid DC (mDC) from MyD88 -/-mice expressed much less IL-6 and IL-23, and serum and T cell IL-17 were absent. TLR4-/-and TLR9 -/-mice surprisingly exhibited more severe EAE symptoms than WT mice. IL-6 and IL-23 expression by mDC and Th17 responses were higher in TLR4 -/-mice, suggesting a regulatory role of TLR4 in priming Th17 cells. IL-6 expression by splenocytes was higher in TLR9 -/-mice. Our data suggest that MyD88 mediates the induction of mDC IL-6 and IL-23 responses after MOG immunization, which in turn drives IL-17-producing encephalitogenic Th17 cell activation. Importantly, we demonstrate that TLR4 and TLR9 regulate disease severity in MOGinduced EAE.

Treatment of experimental autoimmune encephalomyelitis in SJL/J mice with a replicative HSV-1 vector expressing interleukin-5

“…62 T cells from MyD88-negative mice do not express IL-17. 63 This is accordance with our findings that MyD88 is downregulated early during the treatment with HSV vectors expressing Th2 cytokines, and thus might explain why these HSV vectors ameliorated the EAE disease course.…”

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

“…Internalization of IC containing autoantibodies and nucleic acids through BCR and/or FcγRIIB on B cells and through FcγRIIB on DCs could be involved in maintaining autoimmune responses [47]. In EAE, TLR9 pathway is required for disease induction, and TLR9-deficient mice are protected from EAE progression [13,14]. In view of our data, we can propose that TLR7 stimulation induced by RNA-associated antigens may be, at least in part, responsible for the activation of DCs and B cells in EAE and contribute to the propagation of the inflammatory response.…”

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…In support of this, MyD88 knockout mice are completely resistant this disease, since they fail to develop Th1 and Th17, which are essential in the pathogenesis of EAE [54]. However while a role for TLR signalling in the development of myelin specific Th17 cells has been established the stimulatory TLRs for these Th17 cells have not yet been identified [54].…”

“…For example TLR4 knockout mice have greater disease severity which is associated with increased Th17 function [54], while determining the contribution of TLR9 has produced conflicting results [49,54]. In contrast TLR3 stimulation is protective in EAE due to the induction of IFNβ [55] which has led to the suggestion that TLRs inducing interferon is protective, whereas TLR stimulation that leads to proinflammatory cytokine expression adds to disease severity [56].…”