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

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.

The Role of IL-13 and IL-4 in Adipose Tissue Fibrosis

“…BMDMs were generated from bone marrow cells of Il4ra−/− mice and littermate controls ( Il4ra+/+ ). Bone marrow cells were collected by flushing tibias and femurs with PBS and centrifuged for 10 min at 300 g [ 61 ]. Subsequently, the cells were differentiated into macrophages in BMDM medium (RPMI1640 medium supplemented with 10% FBS, 1 mM GlutaMax, 1% penicillin/streptomycin, all from Thermo Fisher Scientific, Waltham, MA, USA) and 20 ng/mL M-CSF (PeproTech, Hamburg, Germany) at 37 °C with 5% CO 2 .…”

“…Total RNA was extracted from epididymal WAT and AT explants using the RNeasy Lipid Tissue Mini Kit (Qiagen, Hilden, Germany) followed by cDNA synthesis from 1 µg of total RNA with the First Strand cDNA Synthetis Kit (New England Biolabs) [ 61 ]. Quantitative real-time PCR was performed by using a SYBR green qPCR Master Mix (Thermo) and a ViiA™ 7 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA).…”

Drastic transformation of visceral adipose tissue and peripheral CD4 T cells in obesity

“…In these structures, IL-6 functions as a major driver of proliferation of VAT macrophages in obesity by upregulating IL-4Ra (102). The role of the Th2 cytokines IL-4 and IL-13 in VAT inflammation caused by a HFD load is supported by the finding that inflammation is reduced in mice with myeloid cellspecific knockout of IL-4Ra (103). Thus, in the obese environment, Th2 cytokines play an important role in the maintenance of fast-proliferating macrophages within the crown-like structures (102).…”

Adipose tissue macrophages as potential targets for obesity and metabolic diseases

“…Moreover, an intact IL-4 and IL-13 signaling is required for maturation of alternatively activated ATMs and reducing diet-induced obesity and IR in mice ( 170 , 171 ). However, myeloid cell-specific knockout of IL4R alpha decreased insulin sensitivity in lean mice while improving parameters of glucose homeostasis and partially protecting against adipose tissue inflammation in obese mice ( 172 ), indicating IL-4R signaling likely plays a significant role in maintaining the alternative activation of macrophage in lean conditions but not in obesity.…”