Endothelial AHR-APLNR signaling preserves vascular glycocalyx integrity and limits neutrophil-driven skin injury during local MRSA infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infection, yet the contribution of the cutaneous vasculature to host defense remains incompletely understood. Here, we identify endothelial aryl hydrocarbon receptor (AHR) signaling as a key regulator of vascular integrity and inflammatory responses during local MRSA skin infection. MRSA challenge reduced AHR expression in cutaneous endothelial cells in both human and murine skin. Endothelial-specific AHR deficiency exacerbated skin injury, increased bacterial burden, enhanced inflammatory cytokine production, and promoted neutrophil accumulation and activation. Mechanistically, AHR-deficient endothelial cells induced exaggerated neutrophil calcium signaling and prolonged neutrophil-endothelial interactions during transendothelial migration. Loss of endothelial AHR was further associated with glycocalyx thinning, widened endothelial junctions, and vascular leakage, indicating impaired vascular barrier function. Pharmacological AHR activation partially reversed these abnormalities. Transcriptomic and functional analyses revealed that endothelial AHR maintained apelin receptor (APLNR) expression, whereas pharmacological inhibition of APLNR reproduced several inflammatory and vascular features observed in AHR-deficient mice. Collectively, these findings identify an endothelial AHR-APLNR-glycocalyx pathway that preserves vascular barrier integrity and restrains maladaptive neutrophil activation during MRSA skin infection, highlighting a potential therapeutic target for bacterial skin disease.