JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

Scar wars: Scars developing after skin wound can cause important functional, aesthetic, psychological, and social consequences. The mechanisms mediating scar formation after skin wound remain to be completely elucidated. Here, Griffin et al. showed that pathological scarring induced by overexpressing JUN in mice was mediated by CD36-dependent fibroblast modulation that resulted in increased fibrosis at the site of injury. Pharmacological CD36 inhibition with salvianolic acid B reduced the fibrosis process in human fibroblasts and scar formation in Jun-overexpressing mice. The results suggest that targeting CD36 might be effective in reducing hypertrophic scar formation during skin wound healing. Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I–expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9–mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring. [ABSTRACT FROM AUTHOR]