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

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 (IIl4ra(Delta myel)) of the IL-4 receptor alpha-chain (IL-4R alpha), the mandatory signaling component of IL-4 and IL-13, on chow and high-fat diet. Lean IIl4ra(Delta myel) 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, IIl4ra(Delta myel) 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-4R alpha 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-4R alpha 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.

Automated summary

This study suggests that IL-4 receptor signaling plays a minor role in maintaining the macrophage M2 population and proliferation rates in vivo, while IL-4 signaling exerts a proinflammatory role in adipose tissue inflammation by directly upregulating CD11c on adipose tissue macrophages.