Endogenous N-acyl taurines regulate skin wound healing

Significance Healthy human skin quickly repairs itself when wounded. Skin healing is essential for survival, and it depends on a well-ordered sequence of molecular and cellular events that require the cooperation of several growth-promoting proteins released by skin cells or produced in the extracellular matrix. In the present study, we identify a family of lipid-derived molecules that accelerate the closure of self-repairing skin wounds. These endogenous substances promote migration of epidermal keratinocytes and differentiation of dermal fibroblasts by recruiting intracellular signals similar to those engaged by protein growth factors. Understanding this unprecedented mechanism of wound-healing control may guide new therapeutic approaches to the management of chronic wounds in patients with diabetes, bed-ridden elderly people with pressure ulcers, and immunosuppressed recipients of organ transplants. The intracellular serine amidase, fatty acid amide hydrolase (FAAH), degrades a heterogeneous family of lipid-derived bioactive molecules that include amides of long-chain fatty acids with taurine [N-acyl-taurines (NATs)]. The physiological functions of the NATs are unknown. Here we show that genetic or pharmacological disruption of FAAH activity accelerates skin wound healing in mice and stimulates motogenesis of human keratinocytes and differentiation of human fibroblasts in primary cultures. Using untargeted and targeted lipidomics strategies, we identify two long-chain saturated NATs—N-tetracosanoyl-taurine [NAT(24:0)] and N-eicosanoyl-taurine [NAT(20:0)]—as primary substrates for FAAH in mouse skin, and show that the levels of these substances sharply decrease at the margins of a freshly inflicted wound to increase again as healing begins. Additionally, we demonstrate that local administration of synthetic NATs accelerates wound closure in mice and stimulates repair-associated responses in primary cultures of human keratinocytes and fibroblasts, through a mechanism that involves tyrosine phosphorylation of the epidermal growth factor receptor and an increase in intracellular calcium levels, under the permissive control of transient receptor potential vanilloid-1 receptors. The results point to FAAH-regulated NAT signaling as an unprecedented lipid-based mechanism of wound-healing control in mammalian skin, which might be targeted for chronic wound therapy.