Ining question is how skin bacteria trigger RELM expression in the skin. A number of probable mechanisms are suggested by prior studies of skin and gut antimicrobial proteins. A single possibility is that RELM expression is controlled by host pattern recognition receptors, such as Toll-like receptors (TLR), which are expressed on skin epithelial cells. This idea is suggested by the fact that epithelial cell TLR signaling controls the expression of many epithelial antimicrobial proteins, such as REGIII and RELM inside the gut (Vaishnava et al., 2011) and -defensin around the skin (Sumikawa et al., 2006). Cathelicidin expression is also controlled by TLR signaling, but in an indirect manner. Activation of keratinocyte TLR2 induces expression of the CYP27B1 gene, which encodes 25-hydroxyvitamin D3–hydroxylase. This enzyme controls production on the active form of vitamin D, which binds to the vitamin D receptor (VDR) and promotes transcription in the gene DNA Methyltransferase Inhibitor Formulation encoding cathelicidin (Liu et al., 2006; Schauber et al., 2007). Our obtaining that the vitamin A derivative retinol drives RETN expression via RAR(s) suggests that skin bacteria could similarly regulate retinol or retinoic acid levels in keratinocytes and sebocytes and therefore promote RAR-dependent transcription of RELM-encoding genes. A second possible mechanism requires capture of bacterial signals by pattern recognition receptors on immune cells that patrol the tissues that underlie the skin surface, followed by signaling back for the epidermal layer by way of cytokines. This thought is recommended by studies of intestinal REGIII, whose expression is usually triggered by a cytokine signaling relay among dendritic cells, sort 3 innate lymphoid cells (ILC), and intestinal epithelial cells (Sanos et al., 2009). Similarly, a rich network of skin-resident dendritic cells and ILC resides in the subcutaneous tissues (Belkaid and Segre, 2014; Kobayashi et al., 2019), and could convey HDAC4 Inhibitor site regulatory signals to keratinocytes and sebocytes to regulate RELM expression. A third possibility is that skin bacteria induce RELM protein expression via their metabolic solutions. Within the gut, microbial fermentation of dietary fiber produces quick chain fatty acids (SCFA), which include butyrate, which can alter epithelial cell gene expression (Ganapathy et al., 2013). Despite the fact that the skin surface is normally aerobic, lipid-rich anaerobic environments can arise below particular situations, for instance occlusion of sebaceous follicles (Sanford et al., 2016). Such situations permit for the production of SCFAs by skin bacteria such as P. acnes, which in turn can alter keratinocyte gene expression (Sanford et al., 2019).Author Manuscript Author Manuscript Author Manuscript Author ManuscriptCell Host Microbe. Author manuscript; offered in PMC 2020 June 12.Harris et al.PageThis suggests that SCFAs or other metabolic solutions of skin bacteria could regulate RELM protein expression. The host diet program is a different important environmental factor, in addition to skin bacteria, that regulates RELM expression. Our research of mice fed a vitamin A-deficient diet program uncovered an unexpected requirement for dietary vitamin A in skin expression of RELM. We also identified that expression on the human RETN gene in sebocytes is enhanced by the vitamin A derivative retinol by means of direct binding of RARs to the RETN promoter. RELM and RETN represent distinctive instances of antimicrobial proteins whose expression is regulated by vitamin A or its derivatives, as a result revealing a function for vitam.
