Reg3 expression in the skin is influenced by fibroblast-keratinocyte interplay and gut inflammation

Summary: Abstract Body: Skin diseases often co-occur with gut disorders and bidirectional crosstalk along the skin-gut axis influences both gastrointestinal and skin health. Our recent findings reveal increased susceptibility to gut inflammation after skin injury with increased expression of Regenerating islet-derived 3 γ (REG3g) in the gut. The functional role of REG3g is not well understood and has previously been suggested to have both antimicrobial and anti-inflammatory functions. Here, we examined the response of the skin to gut inflammation by oral administration of dextran sodium sulfate (DSS) to mice. This intervention caused mice to have more severe infections by S. aureus with an increase in colony-forming units in the skin samples. Furthermore, analysis of the skin during gut inflammation and S. aureus infection showed elevated expression of Reg3g and altered expression of pro-inflammatory cytokines Il-6, Il-1b and TNF-alpha. scRNA-seq data from acute murine skin inflammation induced by topical application of S. aureus(DRA015287) identified fibroblasts as a major source of increased Reg3g expression in skin after S. aureus infection, followed by keratinocytes and myeloid cells. Interestingly, conditioned media from fibroblasts enhanced REG3g expression and protein levels in HaCat cell line of human keratinocytes. Taken together, we show for the first time that gut inflammation modulates Reg3g expression in the skin and alters host defense after S. aureus infection. These data begin to model the impact of intestinal inflammation on the skin host defense system and identify fibroblast-keratinocyte communication as an important factor regulating REG3g. Additional studies to better understand the role of REG3g in the skin and the mechanism for communication between gut and skin are ongoing. Marta Palomo-Irigoyen^{1, 2}, Tatsuya Dokoshi¹, Henry Li¹, Tomofumi Numata¹, Kellen Cavagnero¹, Carlos Aguilera¹, Erwin F. Wagner^{2, 3}, Richard L. Gallo¹ 1. Department of Dermatology, University of California San Diego, La Jolla, CA, United States. 2. Department of Dermatology, Medizinische Universitat Wien, Vienna, Vienna, Austria. 3. Department of Laboratory Medicine, Medizinische Universitat Wien, Vienna, Vienna, Austria. Cell Communication Networks and Stromal Biology