title: Endogenous N-acyl taurines regulate skin wound healing.
abstract: 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.
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, 16163 Genoa, Italy;
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, 16163 Genoa, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Pontis
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, 16163 Genoa, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Cutaneous Physiopathology, San Gallicano Dermatological Institute, Istituto di Ricovero e Cura a Carattere Scientifico, 00163 Rome, Italy;
authors.forename: Giorgia
authors.initials: G
authors.lastname: Cardinali
authors.affiliation: Cutaneous Physiopathology, San Gallicano Dermatological Institute, Istituto di Ricovero e Cura a Carattere Scientifico, 00163 Rome, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Kovacs
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, 16163 Genoa, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Migliore
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, 16163 Genoa, Italy;
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.affiliation: Cutaneous Physiopathology, San Gallicano Dermatological Institute, Istituto di Ricovero e Cura a Carattere Scientifico, 00163 Rome, Italy;
authors.forename: Mauro
authors.initials: M
authors.lastname: Picardo
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, 16163 Genoa, Italy; Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697; Department of Pharmacology, University of California, Irvine, CA 92697; Department of Biological Chemistry, University of California, Irvine, CA 92697 piomelli@uci.edu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013379:Substrate Specificity; D013654:Taurine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D013654:Taurine; D000099252:Fatty Acid Amide Hydrolases
keywords: FAAH; FAEs; N-acyl taurines; fibroblasts; keratinocytes