Control of IL-17 receptor signaling and tissue inflammation by the p38α-MKP-1 signaling axis in a mouse model of multiple sclerosis.
T helper 17 (T(H)17) cells, a subset of CD4+ T cells that secrete the proinflammatory cytokine interleukin-17 (IL-17), play a key pathogenic role in autoimmune diseases. Through inducible and tissue-specific deletion systems, we described the time- and tissue-specific roles of the mitogen-activated protein kinase (MAPK) p38α in mediating T(H)17 cell-induced tissue inflammation. Inducible deletion of Mapk14 (which encodes p38α) after the onset of experimental autoimmune encephalomyelitis (EAE), a murine model for human multiple sclerosis, protected mice from inflammation. Furthermore, the severity of EAE was markedly reduced in mice with specific loss of p38α in neuroectoderm-derived cells, including astrocytes, an effect that was associated with defective production of chemokines and decreased infiltration of the target tissue by immune cells. p38α linked IL-17 receptor (IL-17R) signaling to the expression of genes encoding proinflammatory chemokines and cytokines. Mice that lacked MAPK phosphatase 1 (MKP-1), an inhibitor of p38α, had exacerbated EAE and enhanced expression of IL-17R-dependent genes. Our results suggest that the p38α-MKP-1 signaling axis links IL-17R signaling in tissue-resident cells to autoimmune inflammation dependent on infiltrating T(H)17 cells.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.|Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Gonghua
G
Huang
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Yanyan
Y
Wang
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Peter
P
Vogel
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hongbo
H
Chi
D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000276:immunology*; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
C491673:Il17ra protein, mouse; D053722:Receptors, Interleukin-17; D048308:Mitogen-Activated Protein Kinase 14; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse