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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