Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis

European Journal of Immunology - Tập 38 Số 2 - Trang 565-575 - 2008
Mónica Marta1, Åsa Andersson2,3, Magnus Isaksson4, Olle Kämpe4, Anna Lobell5,1
1Neuroimmunology Unit; Department of Clinical Neuroscience; Karolinska Institute; Stockholm Sweden
2Applied Immunology Unit, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
3Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Los Angeles School of Medicine, Los Angeles, CA, USA
4Dept. of Medical Sciences, Uppsala University, Uppsala, Sweden
5Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Tóm tắt

AbstractInnate 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.

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European Journal of Immunology

Tập 38 Số 2

565-575

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