MC1R determines healing outcomes in acute and chronic cutaneous wounds
Abstract
Chronic wounds (CWs) represent a major clinical challenge, characterized by persistent inflammation and failed repair. While proresolving pathways are known to regulate inflammatory responses, their potential dysfunction in CWs remains unexplored. Here, we identify dysregulation of the pro-opiomelanocortin-melanocortin 1 receptor (POMC–MC1R) axis as a common feature across pressure ulcers, venous ulcers, and diabetic ulcers. Using MC1Re/e mice lacking functional MC1R, we demonstrate impaired wound healing marked by delayed reepithelialization and increased neutrophil extracellular traps—pathological features observed in human CWs. To investigate MC1R’s therapeutic potential, we developed a new murine CW model that replicates human pathology, presenting as nonhealing, exudate-rich ulcers. Topical application of the MC1R-selective agonist BMS-470539 restored healing by reducing exudate production, stimulating vascularization, and enabling reepithelialization. The critical role of MC1R was further evidenced by MC1Re/e mice, which developed more severe ulcers with excessive exudate and NETosis. In acute wound studies, we found that topical MC1R agonist enhanced wound bed perfusion and lymphatic drainage through increased angiogenesis and lymphangiogenesis and reduced scarring by modulating fibroblast phenotype. Together, these findings establish the MC1R/POMC axis as a fundamental regulator of skin repair and identify promising therapeutic strategies to drive healing.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Yonlada Nawilaijaroen
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh
Holly R. Rocliffe
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh
Shani Austin-Williams
Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry
Georgios Krilis
Centre for Cardiovascular Research, The Queen’s Medical Research Institute, University of Edinburgh
Charlotte Dawson
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh
Pruistinne Harijanto
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh
Antonella Pellicoro
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh
Kanheng Zhou
School of Science and Engineering, Fulton Building, University of Dundee
Yubo Ji
School of Science and Engineering, Fulton Building, University of Dundee
Connor A. Bain
Institute of Mechanical, Process and Energy Engineering, School of Engineering and Physical Sciences, Heriot-Watt University
Alastair M. Kilpatrick
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh
Yuhang Chen
Center of Advanced Electrochemical Energy, State Key Laboratory of Advanced Chemical Power Sources, School of Chemistry and Chemical Engineering
Asok Biswas
Department of Pathology, Western General Hospital
Shareen Forbes
Centre for Cardiovascular Research, The Queen’s Medical Research Institute, University of Edinburgh
Michael Crichton
Institute of Mechanical, Process and Energy Engineering, School of Engineering and Physical Sciences, Heriot-Watt University
Zhihong Huang
School of Science and Engineering, Fulton Building, University of Dundee
Stuart J. Forbes
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh
Andrea Caporali
Centre for Cardiovascular Research, The Queen’s Medical Research Institute, University of Edinburgh
Jenna L. Cash
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh