Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss

BACKGROUND:The cytokine thymic stromal lymphopoietin (TSLP) promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown. OBJECTIVE:Here, we investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss. METHODS:RNA sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single cell RNA sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro. RESULTS:We found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single cell RNA sequencing revealed that TSLP recruited distinct T cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro. CONCLUSION:We propose that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss. CLINICAL IMPLICATION:Thus, beyond causing skin inflammation, IL-4 and IL-13 can also promote sebum secretion, which is an important component of the skin barrier.