Research ArticleInflammation

Control of IL-17 receptor signaling and tissue inflammation by the p38α–MKP-1 signaling axis in a mouse model of multiple sclerosis

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Science Signaling  03 Mar 2015:
Vol. 8, Issue 366, pp. ra24
DOI: 10.1126/scisignal.aaa2147


T helper 17 (TH17) 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 TH17 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 TH17 cells.

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