Increased glucocorticoid activation during mouse skin wound healing

Glucocorticoid (GC) excess inhibits wound healing causing increased patient discomfort and infection risk. 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) activates GCs (converting 11-dehydrocorticosterone to corticosterone in rodents) in many tissues including skin, where de novo steroidogenesis from cholesterol has also been reported. To examine the regulation of 11 beta-HSD1 and steroidogenic enzyme expression during wound healing, 5 mm wounds were generated in female SKH1 mice and compared at days 0, 2, 4, 8, 14, and 21 relative to unwounded skin. 11 beta-HSD1 expression (mRNA and protein) and enzyme activity were elevated at 2 and 4 days post-wounding, with 11 beta-HSD1 localizing to infiltrating inflammatory cells. 11 beta-HSD2 (GC-deactivating) mRNA expression and activity were undetectable. Although several steroidogenic enzymes displayed variable expression during healing, expression of the final enzyme required for the conversion of 11-deoxycorticosterone to corticosterone, 11 beta-hydroxylase (CYP11B1), was lacking in unwounded skin and post-wounding. Consequently, 11-deoxycorticosterone was the principal progesterone metabolite in mouse skin before and after wounding. Our findings demonstrate that 11 beta-HSD1 activates considerably more corticosterone than is generated de novo from progesterone in mouse skin and drives GC exposure during healing, demonstrating the basis for 11 beta-HSD1 inhibitors to accelerate wound repair.