Loss of epidermal microRNA-149 sensitizes to skin inflammation

MicroRNAs (miRNAs) are critical regulators of skin inflammation and immune response, yet the intrinsic roles of many miRNAs remain undefined. Here, we show that epidermal deletion of miR-149 (Mir149EKO) predisposes the skin to a pre-inflammatory state by derepressing Tweak/Tweakr signaling. Although loss of epidermal miR 149 is tolerated in maintaining skin homeostasis without overt developmental abnormalities, miR-149-deficient keratinocytes exhibit an altered transcriptomic profile with elevated Tweakr levels, rendering them hyperresponsive to Tweak stimulation and driving heightened NF-κB activation and chemokine production. Upon imiquimod or IL-23 challenge, Mir149EKO mice develop exacerbated psoriasiform inflammation characterized by pronounced epidermal thickening, increased immune infiltration, and upregulation of inflammatory mediators. Single-cell transcriptomic analysis further reveals an expanded basal keratinocytes population with enriched Tweak signaling signatures and increased mast cells infiltration in Mir149EKO skin. Notably, selective mast cell targeting with monensin reduces imiquimod-induced skin inflammation, while Tweak neutralization effectively ameliorates the inflammatory phenotype and abolishes mast cell accumulation in Mir149EKO mice. Collectively, these findings demonstrate that miR-149 acts as an intrinsic break on the epithelial immune response, and its suppression leads to increased susceptibility to inflammation.