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

Ilgiz A. Mufazalov, David Andruszewski, Carsten Schelmbauer, Sylvia Heink, Michaela Blanfeld, Joumana Masri, Yilang Tang, Rebecca Schüler, Christina Eich, F. Thomas Wunderlich, Susanne H. Karbach, Jeffrey A. Bluestone, Thomas Korn and Ari Waisman
J Immunol February 15, 2020, 204 (4) 747-751; DOI: https://doi.org/10.4049/jimmunol.1900876
Ilgiz A. Mufazalov
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
†Diabetes Center, University of California, San Francisco, CA 94143;
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David Andruszewski
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Carsten Schelmbauer
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Sylvia Heink
‡Abteilung für Experimentelle Neuroimmunologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany;
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Michaela Blanfeld
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Joumana Masri
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Yilang Tang
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Rebecca Schüler
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
§Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
¶Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Christina Eich
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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F. Thomas Wunderlich
‖Max Planck Institute for Metabolism Research, Cologne Cluster of Excellence in Aging-Associated Diseases, Institute for Genetics, 50931 Cologne, Germany;
#Center for Molecular Medicine Cologne, Institute for Genetics, University of Cologne, 50931 Cologne, Germany; and
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Susanne H. Karbach
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
§Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
¶Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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Jeffrey A. Bluestone
†Diabetes Center, University of California, San Francisco, CA 94143;
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Thomas Korn
‡Abteilung für Experimentelle Neuroimmunologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany;
**Munich Cluster for Systems Neurology, SyNergy, 81377 Munich, Germany
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Ari Waisman
*Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany;
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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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The Journal of Immunology: 204 (4)
The Journal of Immunology
Vol. 204, Issue 4
15 Feb 2020
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Cutting Edge: IL-6–Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression
Ilgiz A. Mufazalov, David Andruszewski, Carsten Schelmbauer, Sylvia Heink, Michaela Blanfeld, Joumana Masri, Yilang Tang, Rebecca Schüler, Christina Eich, F. Thomas Wunderlich, Susanne H. Karbach, Jeffrey A. Bluestone, Thomas Korn, Ari Waisman
The Journal of Immunology February 15, 2020, 204 (4) 747-751; DOI: 10.4049/jimmunol.1900876

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Cutting Edge: IL-6–Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression
Ilgiz A. Mufazalov, David Andruszewski, Carsten Schelmbauer, Sylvia Heink, Michaela Blanfeld, Joumana Masri, Yilang Tang, Rebecca Schüler, Christina Eich, F. Thomas Wunderlich, Susanne H. Karbach, Jeffrey A. Bluestone, Thomas Korn, Ari Waisman
The Journal of Immunology February 15, 2020, 204 (4) 747-751; DOI: 10.4049/jimmunol.1900876
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