Key Points
Constitutive IL-6 overproduction promotes myeloid cell–driven inflammation.
IL-6Rα (CD126) is indispensable for IL-6–mediated STAT3 activation in mice.
Abstract
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.
Footnotes
↵1 T.K. and A.W. coshared authorship.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (TRR128-A07 [to A.W. and T.K.]). In addition, T.K. was supported by the DFG Grant SFB1054-B06 and the Munich Cluster for Systems Neurology as well as by the European Research Council (CoG 647215) and the Federal Ministry of Education and Research (01GI1605B). A.W. was, in addition, supported by the DFG Grants WA1600/10-1 and TRR128-A03. S.H.K. was supported by the Margarethe Waitz-Foundation, the DFG Grant KA4035/1-1, by the Boehringer Ingelheim Foundation “Novel and Neglected Cardiovascular Risk Factors: Molecular Mechanisms and Therapeutic Implications,” and by the German Center of Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf- Forschung) “Platelet Signatures and Psoriasis in Cardiac Dysfunction.” S.H.K. was also supported by the Federal Ministry of Education and Research (BMBF 01EO1503), related to this study. I.A.M. and J.A.B. were supported by the Sean N. Parker Autoimmunity Research Laboratory.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- DC
- dendritic cell
- IL-6Rα
- IL-6R α-chain
- OE
- overexpression
- VD−
- viability dye–negative.
- Received July 29, 2019.
- Accepted December 15, 2019.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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