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Myeloid Cell–Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation

Jan Ackermann, Lilli Arndt, Michaela Kirstein, Constance Hobusch, Georg Brinker, Nora Klöting, Julia Braune and Martin Gericke
J Immunol December 15, 2021, 207 (12) 3081-3089; DOI: https://doi.org/10.4049/jimmunol.2100699
Jan Ackermann
*Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
†Institute of Anatomy, Leipzig University, Leipzig, Germany;
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Lilli Arndt
*Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
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Michaela Kirstein
*Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
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Constance Hobusch
†Institute of Anatomy, Leipzig University, Leipzig, Germany;
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Georg Brinker
*Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
†Institute of Anatomy, Leipzig University, Leipzig, Germany;
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Nora Klöting
‡Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig; and
§Medical Department III, Leipzig University, Leipzig, Germany
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Julia Braune
*Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
†Institute of Anatomy, Leipzig University, Leipzig, Germany;
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Martin Gericke
*Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
†Institute of Anatomy, Leipzig University, Leipzig, Germany;
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Key Points

  • Lean Il4raΔmyel mice have a deteriorated insulin sensitivity.

  • Obese Il4raΔmyel mice have a rather improved metabolic phenotype.

  • IL-13 stimulation increases CD11c expression in macrophages.

Abstract

IL-4 receptor signaling is supposed to play a major role in anti-inflammatory polarization and proliferation of adipose tissue macrophages. In this study, we examined the metabolic and inflammatory phenotype of C57BL/6J mice (IIl4ra) with LysM-dependent knockout (IIl4raΔmyel) of the IL-4 receptor α-chain (IL-4Rα), the mandatory signaling component of IL-4 and IL-13, on chow and high-fat diet. Lean IIl4raΔmyel mice showed decreased insulin sensitivity, no divergent adipose tissue macrophage polarization, but an increased percentage of CD8+ T cells in visceral adipose tissue. After 20 wk of a high-fat diet, IIl4raΔmyel mice exhibited higher glucose tolerance, no changes in the lymphocyte compartment and fewer M1 macrophages in visceral adipose tissue. In vivo adipose tissue macrophage proliferation measured by BrdU incorporation was unaffected by Il4ra knockout. Interestingly, we show that IL-4Rα signaling directly augmented Itgax (Cd11c) gene expression in bone marrow–derived macrophages and increased the amount of CD11c+ macrophages in adipose tissue explants. Myeloid cell–specific knockout of Il4ra deteriorated insulin sensitivity in lean mice but improved parameters of glucose homeostasis and partially protected from adipose tissue inflammation in obese mice. Hence, IL-4Rα signaling probably plays a minor role in maintaining the macrophage M2 population and proliferation rates in vivo. Moreover, our data indicate that IL-4 signaling plays a proinflammatory role in adipose tissue inflammation by directly upregulating CD11c on adipose tissue macrophages.

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Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; Projektnummer 209933838 – Collaborative Research Center (SFB) 1052) (project B1 to M.G., B4 to N.K., and B9 to M.G.) and supported by the Federal Ministry of Education and Research, Germany, Integrated Research and Treatment Center (IFB) AdiposityDiseases 01EO1501. This research work was supported by the research group “SFB1052/2” B1 (to M.G.); B4 (to N.K.) funded by Deutsche Forschungsgemeinschaft and supported by the Federal Ministry of Education and Research, Germany, IFB AdiposityDiseases 01EO1501 (N.K.), German Research Center for Diabetes (82DZD00601), and German Diabetes Association (934300-003) and by a student fellowship to J.A.

  • J.B. and M.G. designed and established the experiments; J.A., L.A., M.K., C.H., and J.B. performed the experiments; G.B. helped with flow cytometry; N.K. determined the genotypes of the IIl4raΔmyel mouse strain, managed activity measurements, indirect calorimetry, and helped with analytical procedures; and J.A., J.B. and M.G. wrote the manuscript.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    ARG1
    arginase-1
    AT
    adipose tissue
    ATM
    adipose tissue macrophage
    ATT
    AT T cell
    BAT
    brown adipose tissue
    BMDM
    bone marrow–derived macrophage
    CLS
    crown-like structure
    HFD
    high-fat diet
    ipGTT
    i.p. glucose tolerance test
    ipITT
    i.p. insulin tolerance test
    M1
    classically activated
    M2
    alternatively activated
    PWAT
    peritoneal white AT
    SWAT
    s.c. white AT
    YFP
    yellow fluorescent protein

  • Received July 14, 2021.
  • Accepted October 18, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 207 (12)
The Journal of Immunology
Vol. 207, Issue 12
15 Dec 2021
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Myeloid Cell–Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation
Jan Ackermann, Lilli Arndt, Michaela Kirstein, Constance Hobusch, Georg Brinker, Nora Klöting, Julia Braune, Martin Gericke
The Journal of Immunology December 15, 2021, 207 (12) 3081-3089; DOI: 10.4049/jimmunol.2100699

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Myeloid Cell–Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation
Jan Ackermann, Lilli Arndt, Michaela Kirstein, Constance Hobusch, Georg Brinker, Nora Klöting, Julia Braune, Martin Gericke
The Journal of Immunology December 15, 2021, 207 (12) 3081-3089; DOI: 10.4049/jimmunol.2100699
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