TY - JOUR
T1 - Cutting edge
T2 - IL-6-driven immune dysregulation is strictly dependent on IL-6R a-chain expression
AU - Mufazalov, Ilgiz A.
AU - Andruszewski, David
AU - Schelmbauer, Carsten
AU - Heink, Sylvia
AU - Blanfeld, Michaela
AU - Masri, Joumana
AU - Tang, Yilang
AU - Schüler, Rebecca
AU - Eich, Christina
AU - Wunderlich, F. Thomas
AU - Karbach, Susanne H.
AU - Bluestone, Jeffrey A.
AU - Korn, Thomas
AU - Waisman, Ari
N1 - Publisher Copyright:
Copyright Ó 2020 by The American Association of Immunologists, Inc.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - IL-6 binds to the IL-6R a-chain (IL-6Ra) 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-6Ra. 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-6Ra protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6Ra-deficient mice without IL-6 overexpression. Mechanistically, IL-6Ra deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6Ra is the only biologically relevant receptor for IL-6 in mice. The Journal of Immunology, 2020, 204: 747-751.
AB - IL-6 binds to the IL-6R a-chain (IL-6Ra) 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-6Ra. 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-6Ra protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6Ra-deficient mice without IL-6 overexpression. Mechanistically, IL-6Ra deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6Ra is the only biologically relevant receptor for IL-6 in mice. The Journal of Immunology, 2020, 204: 747-751.
UR - http://www.scopus.com/inward/record.url?scp=85079021397&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1900876
DO - 10.4049/jimmunol.1900876
M3 - Article
C2 - 31924653
AN - SCOPUS:85079021397
SN - 0022-1767
VL - 204
SP - 747
EP - 751
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -