Cutting Edge: IL-6-Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression.
J Immunol. 2020 Jan 10. pii: ji1900876. doi: 10.4049/jimmunol.1900876. [Epub ahead of print]
|Authors/Editors:||Mufazalov IA, Andruszewski D, Schelmbauer C, Heink S, Blanfeld M, Masri J, Tang Y, Schüler R, Eich C, Wunderlich FT, Karbach SH, Bluestone JA, Korn T, Waisman A.|
IL-6 binds to the IL-6R α-chain (IL-6Rα) and signals via the signal transducer gp130. Recently, IL-6 was found to also bind to the cell surface glycoprotein CD5, which would then engage gp130 in the absence of IL-6Rα. However, the biological relevance of this alternative pathway is under debate. In this study, we developed a mouse model, in which murine IL-6 is overexpressed in a CD11c-Cre–dependent manner. Transgenic mice developed a lethal immune dysregulation syndrome with increased numbers of Ly-6G+ neutrophils and Ly-6Chi monocytes/macrophages. IL-6 overexpression promoted activation of CD4+ T cells while suppressing CD5+ B-1a cell development. However, additional ablation of IL-6Rα protected IL-6–overexpressing mice from IL-6–triggered inflammation and fully phenocopied IL-6Rα–deficient mice without IL-6 overexpression. Mechanistically, IL-6Rα deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6Rα is the only biologically relevant receptor for IL-6 in mice.