Skin resident macrophage-derived microRNA21 drives susceptibility to Staphylococcus-aureus infection.

Abstract

Abstract Staphylococcus aureus skin infection is orchestrated by the actions of resident and recruited immune cells that lead to abscess formation and bacteria contained. Modulation of the immune response can be achieved by microRNAs. MicroRNA21 (miR21) is a homeostatic regulator of macrophage polarization and miR21 could modulate the expression of either pro- or anti-inflammatory mediators. We are hypothesizing that miR21 is a central node between the regulation of the inflammatory response and antimicrobial effectors functions in the skin. Our data show that miR21 increases as early as 12h, peaks at 24h and 48h. The depletion of skin resident macrophages, but not recruited neutrophils, showed a specific role of skin macrophages in miR21 expression during skin infection. Skin infection in miR21Δmyel mice resulted in reduced lesion size and lower bacterial burden when compared to WT animals. We detected increased IL-1ß and TNF-α and decreased IL-6 and IL-1α levels in the skin of miR21 deficient mice. We also observed increased expression of pro-resolution genes, such as CD36 and collagen3a1 at day 1 after infection. The balance between proinflammatory cytokines, along with the presence of collagen 3 and CD36, resulted in a highly organized abscess with ticker capsule when compared to infected WT mice. Topical treatment with a miR21 antagomir induces reduced lesion size and bacterial burden. Nanostring analysis showed increased Myd88 expression in both naïve and S. aureus infected miR21Δmyel mice and blocking MyD88 actions prevented miR21 antagomir-mediated bacterial clearance in vivo. Our results show blocking miR21 expression leads to a well-controlled inflammatory response necessary to control skin bacterial host defense. Supported by FAPESP 2018/01622-9, HL-103777, R01HL124159-01