An epidermal-specific role for arginase1 during cutaneous wound repair

Abstract

Non-healing wounds are a major area of unmet clinical need remaining problematic to treat. Improved understanding of pro-healing mechanisms is invaluable. The enzyme arginase1 is involved in pro-healing responses with its role in macrophages best characterized. Arginase1 is also expressed by keratinocytes; however, arginase1 function in these critical wound repair cells is not understood. We characterized arginase1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal arginase1 expression was decreased in both human and murine delayed healing wounds. We therefore generated a keratinocyte specific arginase1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration and differentiation, was significantly delayed in K14-cre;Arg1fl/fl mice. Similarly, using the arginase inhibitor nor-NOHA, human in vitro and ex vivo models further confirmed this finding, revealing the importance of the downstream polyamine pathway in repair. Indeed, restoring the balance in arginase1 activity via addition of putrescine, proved beneficial in wound closure. In summary, we demonstrate that epidermal arginase1 plays a, to our knowledge, previously unreported intrinsic role in cutaneous healing, highlighting epidermal arginase1 and downstream mediators as potential targets for the therapeutic modulation of wound repair.