TY - JOUR
T1 - Endogenous N- Acyl taurines regulate skin wound healing
AU - Sasso, Oscar
AU - Pontis, Silvia
AU - Armirotti, Andrea
AU - Cardinali, Giorgia
AU - Kovacs, Daniela
AU - Migliore, Marco
AU - Summa, Maria
AU - Moreno-Sanz, Guillermo
AU - Picardo, Mauro
AU - Piomelli, Daniele
PY - 2016/7/26
Y1 - 2016/7/26
N2 - 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 longchain 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 woundhealing control in mammalian skin, which might be targeted for chronic wound therapy.
AB - 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 longchain 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 woundhealing control in mammalian skin, which might be targeted for chronic wound therapy.
KW - FAAH
KW - FAES
KW - Fibroblasts
KW - Keratinocytes
KW - N- Acyl taurines
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U2 - 10.1073/pnas.1605578113
DO - 10.1073/pnas.1605578113
M3 - Article
AN - SCOPUS:84979500793
VL - 113
SP - E4397-E4406
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 30
ER -