Skin microbiome regulation of the sebum-immune axis

Summary The skin forms a protective barrier against harmful substances and pathogens that we contact through our immediate environment. Specialized glands in the skin known as sebaceous glands secrete sebum, a lipid-rich substance with anti-microbial peptides (AMPs) that enhances the physical, chemical, and immunologic barrier function of the skin. This proposal describes a 5-year research plan focusing on the novel concept that the skin microbiome regulates a newly described immune-mediated sebum axis as a feedback mechanism to enhance skin barrier function and to create an optimal skin microenvironment. We have recently reported that sebum secretion can be regulated by immune cells in response to a keratinocyte-derived cytokine called thymic stromal lymphopoietin (TSLP). In this process, which we call the immune-sebum axis, TSLP stimulates T cells directly through their TSLP receptor (TSLP-R), which induces their migration to the sebaceous glands to promote sebum secretion in an IL-4/13-dependent manner. We now provide preliminary data suggesting that the trigger of the immune-sebum axis could be the skin microbiome. We find that compared to conventionally raised mice, the skin of germ-free mice contains significantly fewer T cells, exhibits ~50% reduction in sebum secretion, and displays lower expression of TSLP, sebum synthesis- related genes, and AMPs. In addition, we found that mice lacking the IL-1 receptor or MyD88 (a molecule critical for signaling downstream of IL-1 family cytokine receptors and Toll-like receptors) also display ~50% reduction in sebum secretion. Thus, we propose that a feedback mechanism exists to maintain homeostasis of the skin microenvironment, whereby skin microbes promote sebum secretion, which in turn controls their growth. Based on these preliminary data, we hypothesize that skin microbes induce the IL-1/MyD88 signaling pathway in the skin to promote sebum secretion and skin barrier function in a TSLP- stimulated T cell-derived IL-4/13-dependent manner. We will test this hypothesis in 3 separate aims. Aim 1 will investigate how the skin microbiota and MyD88 regulate sebum secretion. Aim 2 will probe how IL-4/13 derived from TSLP-stimulated T cells affects sebaceous gland function. Aim 3 will test whether the skin microbiota and TSLP affect skin barrier function and protects against pathogenic skin infection in a sebum- dependent manner. This multidisciplinary project will be led by two co-PIs (Drs. Kambayashi and Grice), who share complementary expertise. Dr. Kambayashi is an expert in T cell biology, cellular immunology, and signal transduction. Dr. Grice is an expert in skin barrier function and skin microbiota. Other collaborators include Dr. Amanda Nelson, as an expert in sebaceous gland biology and Dr. Sunny Wong as an expert in sebaceous gland development. This investigation will provide novel insight into how the skin microbiome engages both the innate and adaptive immune system to promote optimal skin barrier function for the host.