title: Loss of Sprouty4 in T cells ameliorates experimental autoimmune encephalomyelitis in mice by negatively regulating IL-1β receptor expression.
abstract: Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. To gain pathogenicity, however, Th17 cells require IL-1β and IL-23. The underlying mechanism by which these confer pathogenicity is not well understood. Here we show that Sprouty4, an inhibitor of the PLCγ-ERK pathway, critically regulates inflammatory Th17 (iTh17) cell differentiation. Sprouty4-deficient mice, as well as mice adoptively transferred with Sprouty4-deficient T cells, were resistant to experimental autoimmune encephalitis (EAE) and showed decreased Th17 cell generation in vivo. In vitro, Sprouty4 deficiency did not severely affect TGF-β/IL-6-induced Th17 cell generation but strongly impaired Th17 differentiation induced by IL-1/IL-6/IL-23. Analysis of Th17-related gene expression revealed that Sprouty4-deficient Th17 cells expressed lower levels of IL-1R1 and IL-23R, while RORγt levels were similar. Consistently, overexpression of Sprouty4 or pharmacological inhibition of ERK upregulated IL-1R1 expression in primary T cells. Thus, Sprouty4 and ERK play a critical role in developing iTh17 cells in Th17 cell-driven autoimmune diseases.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fukaya
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Someya
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Sana
authors.initials: S
authors.lastname: Hibino
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Humitsugu
authors.initials: H
authors.lastname: Yamane
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075, Japan. Electronic address: yoshimura@a6.keio.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D053573:Receptors, Interleukin-1 Type I; C499037:Spry4 protein, mouse
keywords: Cytokine signaling; ERK; Helper T cells; IL-1 receptor; Th17