MicroRNA-21 restrains myD88-dependent protective inflammation worsening Staphylococcus aureus skin infection

Staphylococcus aureus skin infections are driven by tissue-resident and recruited immune cells. A proper immune response requires a tightly regulated balance between inflammatory responses and the prevention of tissue damage. MicroRNAs are key post-transcriptional regulators of immune responses and influence both pro- and anti-inflammatory pathways. We show that S. aureus skin infection elevates miR-21 levels in the skin, and applying a topical miR-21 antagomir improves bacterial clearance and resolution of skin infection. In MRSA-infected mice lacking miR-21 in myeloid cells (miR21 ^Δmyel ), lesions are smaller, bacterial load decreases, macrophage infiltration is reduced, and collagen around the abscess increases. MiR-21 helps shape the inflammatory environment by modulating mediators such as IL-1β, TNF, IL-33, and IL-10. Additionally, miR-21 deficiency increases MyD88 expression in infected skin, and blocking MyD88 actions abolishes the protective effects observed in miR21 ^Δmyel mice. Overall, the miR-21/MyD88 pathway is a key regulator of the resolution of inflammation and antibacterial immunity during S. aureus skin infections, highlighting miR-21 inhibition as a promising therapy for antibiotic-resistant S. aureus infections.