Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis
Tóm tắt
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 MOG‐induced EAE.
Từ khóa
Tài liệu tham khảo
Lobell A., 1999, Presence of CpG DNA and the local cytokine milieu determine the efficacy of suppressive DNA vaccination in experimental autoimmune encephalomyelitis., J. Immunol., 163, 4754, 10.4049/jimmunol.163.9.4754
Vallin H., 1999, Anti‐double‐stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN‐alpha inducer in systemic lupus erythematosus., J. Immunol., 163, 6306, 10.4049/jimmunol.163.11.6306
Willenborg D. O., 1996, IFN‐gamma plays a critical down‐regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein‐induced autoimmune encephalomyelitis., J. Immunol., 157, 3223, 10.4049/jimmunol.157.8.3223