The trigger and homeostatic function of a novel immune-sebum circuit

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PROJECT SUMMARY Sebum provides vital functions to the skin including moisture retention and defense against foreign inva- sion. Despite the well-defined immunologic function of sebum, immune system regulation of sebum’s role in cutaneous homeostasis is unknown. A lipid-rich substance produced in sebaceous glands (SGs), sebum con- tains fatty acids and induces antimicrobial peptide expression. Sebum secretion increases with puberty onset and is thereafter regulated in part by androgenic hormones. Sebum hypersecretion predisposes to acne vulgaris, whereas insufficiency could disrupt skin barrier function as seen in atopic dermatitis. As current therapeutics targeting SGs can be harmful and often ineffective, there is a critical need for further research into additional mediators of sebum secretion, without which clinical treatment of sebum dysregulation remains lacking. We have found that absence of the keratinocyte derived cytokine thymic stromal lymphopoietin (TSLP) receptor disrupts sebum secretion and that signaling occurs through T cells, supporting the existence of an immune-sebum regulatory circuit. We propose to identify the activating signal that mediates this T cell response and initiates immune-sebum regulation. Skin commensal bacterial communities promote tissue-specific immune system development, including generation of tissue-resident, microbial-specific T cells. It is possible that the skin microbiome is involved in regulating SG function through T cell activation. Indeed, preliminary results show that germ-free (GF) mice secrete less sebum than controls. This leads to the overall hypothesis that skin microbiota induces TSLP-mediated, microbial-specific T cell-dependent sebum secretion, promoting skin barrier function and acting as an important homeostatic innate defense against skin infection. Aim 1 involves conventionalizing GF mice with skin commensal bacteria from controls to determine the necessity of skin microbiota for appropriate sebum secretion. Transgenic murine models will be used with bacteria engineered to express an ovalbumin antigen to determine if regulation occurs through microbiota-specific T cells. In Aim 2, TSLP receptor knockout mice will be used to determine if, at homeostasis, TSLP-mediated sebum secretion (1) promotes skin barrier function by measuring transepidermal water loss, hydration and pH, and (2) prevents infection in a Staphylococ- cus aureus epidermal infection model. This research will form a foundation to allow identification of novel thera- peutic targets for common cutaneous conditions associated with sebum dysregulation. In order to complete these experiments and further my development as a physician-scientist, a rigorous training plan has been proposed focused on the refinement of my experimental design and implementation, scientific communication, research collaboration, and mentorship skills. This training will take place at the Uni- versity of Pennsylvania where I will continue to improve my integration of scientific research and patient care with the guidance and programming offered by the Medical Scientist Training Program. This presents a highly innovative and resource rich environment for me to develop as a future dermatologist-scientist.