Ining question is how skin bacteria trigger RELM expression within the skin. A number of possible mechanisms are suggested by prior studies of skin and gut antimicrobial proteins. 1 possibility is that RELM expression is controlled by host pattern recognition receptors, for example Toll-like receptors (TLR), which are expressed on skin epithelial cells. This notion is recommended by the fact that epithelial cell TLR signaling controls the expression of a number of epithelial antimicrobial proteins, for example REGIII and RELM within the gut (Vaishnava et al., 2011) and -defensin on 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 with the CYP27B1 gene, which encodes 25-hydroxyvitamin H3 Receptor Antagonist Compound D3–hydroxylase. This enzyme controls production in the active type of vitamin D, which binds to the vitamin D receptor (VDR) and promotes transcription of the gene encoding cathelicidin (Liu et al., 2006; Schauber et al., 2007). Our obtaining that the vitamin A derivative retinol drives RETN expression by way of RAR(s) suggests that skin bacteria could similarly regulate retinol or retinoic acid levels in keratinocytes and sebocytes and thus market RAR-dependent transcription of RELM-encoding genes. A second probable 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 to the epidermal layer via cytokines. This thought is suggested by studies of intestinal REGIII, whose expression may be triggered by a cytokine signaling relay amongst dendritic cells, sort three innate lymphoid cells (ILC), and intestinal epithelial cells (Sanos et al., 2009). Similarly, a wealthy network of skin-resident dendritic cells and ILC resides inside the subcutaneous tissues (Belkaid and Segre, 2014; Kobayashi et al., 2019), and could convey regulatory signals to keratinocytes and sebocytes to regulate RELM expression. A third possibility is the fact that skin bacteria induce RELM protein expression by way of their metabolic products. Within the gut, microbial fermentation of Bradykinin B2 Receptor (B2R) Modulator review dietary fiber produces brief chain fatty acids (SCFA), which include butyrate, which can alter epithelial cell gene expression (Ganapathy et al., 2013). While the skin surface is normally aerobic, lipid-rich anaerobic environments can arise below certain situations, such as occlusion of sebaceous follicles (Sanford et al., 2016). Such circumstances let 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; accessible in PMC 2020 June 12.Harris et al.PageThis suggests that SCFAs or other metabolic products of skin bacteria could regulate RELM protein expression. The host diet regime is one more critical environmental element, as well as skin bacteria, that regulates RELM expression. Our studies of mice fed a vitamin A-deficient diet plan uncovered an unexpected requirement for dietary vitamin A in skin expression of RELM. We also discovered that expression of your human RETN gene in sebocytes is enhanced by the vitamin A derivative retinol via direct binding of RARs to the RETN promoter. RELM and RETN represent exclusive situations of antimicrobial proteins whose expression is regulated by vitamin A or its derivatives, hence revealing a function for vitam.
