Cutting Edge: IL-6-Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression

Mufazalov, Ilgiz A.; Andruszewski, David; Schelmbauer, Carsten; Heink, Sylvia; Blanfeld, Michaela; Masri, Joumana; Tang, Yilang; Schueler, Rebecca; Eich, Christina; Wunderlich, F. Thomas; Karbach, Susanne H.; Bluestone, Jeffrey A.; Korn, Thomas und Waisman, Ari (2020): Cutting Edge: IL-6-Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression. In: Journal of Immunology, Bd. 204, Nr. 4: S. 747-751

Abstract

IL-6 binds to the IL-6R alpha-chain (IL-6R alpha) 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-6R alpha. 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-6C(hi) monocytes/macrophages. IL-6 overexpression promoted activation of CD4(+) T cells while suppressing CD5(+) B-1a cell development. However, additional ablation of IL-6R alpha protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6R alpha-deficient mice without IL-6 overexpression. Mechanistically, IL-6R alpha deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6R alpha is the only biologically relevant receptor for IL-6 in mice.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198