A Keratinocyte‐Mast Cell NF‐κB2/CXCL2/IL‐6 Amplification Loop Enhances Cutaneous Antifungal Defense Against C. albicans

mice developed more severe infection than wild-type (WT) controls, and adoptive transfer of bone marrow-derived mast cells (BMMCs) restored antifungal capacity, establishing a critical protective role for MCs in cutaneous C. albicans infection. Mechanistically, MCs secrete IL-6 to drive antimicrobial peptide (AMP) production by keratinocytes (KCs). Reciprocally, KCs activate the non-canonical NF-κB (NF-κB2) pathway and release CXCL2, which signals through CXCR2 on MCs to further promote IL-6 secretion, establishing an NF-κB2-CXCL2-IL-6 amplification loop between the two cell types. Topical recombinant IL-6 enhanced KC-mediated antifungal activity and ameliorated cutaneous C. albicans infection in MC-deficient mice, underscoring the essential, non-redundant role of MC-derived IL-6 in this axis. Collectively, our findings reveal an MC-KC amplification loop centered on the NF-κB2-CXCL2-IL-6 axis that orchestrates cutaneous antifungal defense and identify new therapeutic targets for cutaneous fungal infection.