Jordan Harris

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

Jordan Harris, Taku Kambayashi and Elizabeth Grice

Sebum provides vital cutaneous functions including moisture retention and defense against foreign invaders. Despite the well-defined immunologic function of sebum, immune system involvement in sebum regulation is unknown. Sebum hypersecretion predisposes to the common condition acne vulgaris for which current therapeutics can be harmful and ineffective. There is a critical need for research into additional mediators of sebum secretion, without which clinical treatment of sebum dysregulation remains lacking. We found that the keratinocyte-derived cytokine thymic stromal lymphopoietin (TSLP) promotes sebum secretion through T cell stimulation. TSLP- and T cell-deficient mice display reduced sebum secretion, suggesting an immunologic role in sebum homeostasis. Why does this circuit exist? Analogous intestinal studies show goblet cell mucus secretion can act as an immunologic mediator by regulating growth of gut microbiota. A similar circuit may exist in the skin. Therefore, I hypothesize that the skin microbiome induces TSLP-mediated, microbial-specific T cell-dependent sebum secretion, promoting skin barrier function and acting as a homeostatic defense against cutaneous infection. To investigate if microbiome presence is necessary for sebum secretion, I used germ-free (GF) and antibiotic models to deplete the skin microbiome. I found that GF mice secrete less sebum at baseline. Sebum secretion was not rescued with microbiota conventionalization or reduced with antibiotic treatment in adult mice. These data may emphasize the importance of early-life immune- microbe interactions in triggering this circuit. Future experiments will investigate how neonatal microbiota alteration affects long-term sebum secretion and which circuit components are affected by the skin microbiota. Functionally, interrogation of skin barrier properties including trans- epidermal water loss and hydration were not impacted by gain- or loss-of-function of this immune- sebum circuit. I plan to investigate cutaneous infection susceptibility and microbiome community composition with various TSLP-mediated sebum secretion phenotypes to identify alternative circuit functions. By studying this homeostatic immune-sebum circuit, novel therapeutic targets for sebum-dysregulation diseases may be identified and utilized to improve patient health and quality of life.