RESUMO
Sebaceous glands (SGs) are holocrine glands that produce sebum, which primarily contains lipids that help to maintain the barrier function of the skin. Dysregulated lipid production contributes to the progression of some diseases characterized by dry skin, including atopic dermatitis. Although the lipid production of SGs has been well-studied, few studies have assessed their role in skin immune responses. We found that SGs and sebocytes expressed IL-4 receptor and produced high levels of T helper 2-associated inflammatory mediators after IL-4 treatment, suggesting immunomodulatory effects. Galectin-12 is a lipogenic factor expressed in sebocytes that affects their differentiation and proliferation. Using galectin-12-knockdown sebocytes, we showed that galectin-12 regulated the immune response in cells exposed to IL-4 and promoted CCL26 expression by upregulating peroxisome proliferator-activated receptor-γ. Moreover, galectin-12 suppressed the expression of endoplasmic reticulum stress-response molecules, and CCL26 upregulation by IL-4 was reversed after sebocyte treatment with inducers of endoplasmic reticulum stress, suggesting that galectin-12 controls IL-4 signaling by suppressing endoplasmic reticulum stress. Using galectin-12-knockout mice, we showed that galectin-12 positively regulated the IL-4-induced enlargement of SGs and the development of an atopic dermatitis-like phenotype. Thus, galectin-12 regulates the skin immune response by promoting peroxisome proliferator-activated receptor-γ expression and suppressing endoplasmic reticulum stress in SGs.
RESUMO
Sebaceous glands play an important role in maintaining the skin barrier function by producing lipids. Dysregulated lipid production in these glands may contribute to the pathogenesis of human skin diseases. Galectin-12, a member of the ß-galactosideâbinding lectin family, is preferentially expressed in adipocytes, where it regulates adipogenesis and functions as an intrinsic negative regulator of lipolysis. It is also expressed by sebocytes and contributes to the proliferation of this cell type. In this study, we show the association between galectin-12 expression and sebocyte differentiation. Galectin-12 knockdown in a human sebocyte cell line reduced lipogenesis and decreased the production of cholesteryl esters, triglycerides, free fatty acids, and cholesterol. Metabolomic analysis of skin surface lipids showed that the levels of the lipids mentioned earlier decreased in sebaceous glandâspecific galectin-12âknockout mice compared with that in wild-type mice. In addition, galectin-12 positively regulated peroxisome proliferatorâactivated receptor-γ transcriptional activity in sebocytes stimulated with fatty acids. Downregulating galectin-12 suppressed the expression of peroxisome proliferatorâactivated receptor-γ target genes-acetyl-coenzyme A synthetase 2 gene ACS2 and diacylglycerol O-acyltransferase 1 gene DGAT1-that are required for fatty acid activation and cholesterol and triglyceride biosynthesis. In conclusion, galectin-12 is a positive regulator of sebaceous lipid metabolism with a potential role in the maintenance of skin homeostasis.