Type 2 Immunity Regulates Dermal White Adipose Tissue Function

Type 2 immune responses have been increasingly linked with tissue maintenance, regeneration, and metabolic homeostasis. The molecular basis of regulator and effector mechanisms of type 2 immunity in skin regeneration and homeostasis is still lacking. In this study, we analyzed the role of IL-4Ra signaling in the regeneration of diverse cellular compartments in the skin. Mutants with global IL-4Ra deficiency showed two major phenotypes: first, a pronounced atrophy of the interfollicular epidermis, and second, a significant increase in dermal white adipose tissue thickness in mice aged 3 weeks (postnatal day 21) compared with littermate controls. Notably, IL-4Ra deficiency decreased the activation of hormone-sensitive lipase, a rate-limiting step in lipolysis. Immunohistochemical and FACS analysis in IL-4/enhanced GFP reporter mice showed that IL-4 expression peaked on postnatal day 21 and that eosinophils are the predominant IL-4-expressing cells. Eosinophildeficient mice recapitulated the lipolytic-defective dermal white adipose tissue phenotype of Il4ra-deficient mice, showing that eosinophils are necessary for dermal white adipose tissue lipolysis. Collectively, we provide mechanistic insights into the regulation of interfollicular epidermis and hormone-sensitive lipase-mediated lipolysis in dermal white adipose tissue in early life by IL-4Ra, and our findings show that eosinophils play a critical role in this process.