The Antimicrobial Protein REG3A Regulates Keratinocyte Proliferation and Differentiation after Skin Injury

Abstract

Summary Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by kerati-nocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.

Dendritic epidermal T cells regulate skin antimicrobial barrier function

“…Nonetheless, S100A8 may still play relevant roles during the wound-healing response and may require other IL-17-driven factors for its full function. Expanding previous observations on RegIIIγ (59), we show here that its upregulation is severely compromised not only in Il17a -/-but also in Tcrd -/-mice. Furthermore, WT DETC could restore RegIIIγ expression in Il17a -/-wounds, suggesting that DETC likely provides IL-17A to induce epidermal RegIIIγ upon wounding.…”

“…Recently, a functional role for RegIIIγ has been shown in the cutaneous wound-healing response (59). To directly assess whether β-defensin 3 and S100A8 also affect the wound-healing response, excisional wounds of WT and Il17a -/-mice were treated in vivo with recombinant β-defensin 3 or S100A8 and wound-healing kinetics were measured ( Figure 6E and Supplemental Figure 4).…”

“…Keratinocytes are a rich source of epidermal AMP, which make up a fundamental component of the innate immune system to protect the host from infections in situations where the physical skin barrier is compromised (74). IL-17A produced by DETC subsequently induced epidermal β-defensin 3, S100A8, and RegIIIγ production, which have been shown to function through regulation of keratinocyte migration, energy metabolism, cytoskeletal dynamics, and keratinocyte proliferation and differentiation (59,60,75,76). Induction of AMP was observed as early as 24 hours after wounding, subsequent to IL-17A production by DETC at 18 hours after wounding.…”

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

“…This result is unexpected, because IL-17 has been thought to control primarily the expression of inflammatory and antimicrobial products. However, it was reported recently that the keratinocyte-derived antimicrobial agent RegIIIγ might act as an autocrine/paracrine-acting inducer of keratinocyte proliferation and inhibitor of differentiation (36). Thus it is conceivable that IL-17-induced antimicrobial products also may be involved in regulating the proliferation and differentiation of keratinocytes.…”

Serum 25-hydroxyvitamin D status in pregnant women with chronic hepatitis B virus infection

“…For example, vitamin D can stimulate production of antimicrobial peptides (AMPs) such as α-defensins, β-defensins, and cathelicidin [14,15]. Aside from their direct microbicidal role, AMPs modulate many other immune processes, including mast cell degranulation, cell differentiation, vascular permeability, and the process of antigen presentation [16,17]. Therefore, vitamin D may contribute to HBV-associated liver injury by regulating the innate and/or adaptive immune system.…”