Leucine-enkephalin promotes wound repair through the regulation of hemidesmosome dynamics and matrix metalloprotease

•L-ENK promotes wound healing in human keratinocytes.•Activation of Erk1/2, P90RSK, and Elk-1 are necessary for L-ENK-mediated wound repair.•L-ENK facilitates hemidesmosome disruption.•L-ENK increases MMP-2 and MMP-9 expression. The skin responds to environmental stressors by coordinated actions of neuropeptides and their receptors. An endogenous peptide for δ-opioid receptor (DOPr), Leu-enkephalin (L-ENK), is expressed in the skin and its expression is altered in pathological conditions. Although the importance of DOPr is rapidly gaining recognition, the molecular mechanisms underlying its effects on wound healing are largely undefined. We show here that L-ENK induced activation of Erk, P90RSK, and Elk-1 and promoted the disruption of hemidesmosomes and the expression of matrix metalloprotease (MMP)-2 and MMP-9, important processes for wound healing. Treatment with Erk inhibitor blocked activation of P90RSK and Elk-1 and significantly blunted wound repair. Therefore, our results suggest that activation of Erk and its downstream effectors, P90RSK and Elk-1, are critical for DOPr-mediated skin homeostasis.