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

ABSTRACT Mast cells (MCs), key innate immune sentinels at the host–environment interface, serve as primary responders to invading pathogens. However, their specific contribution to host defense against cutaneous Candida albicans ( C. albicans ) infection and their synergy with other immune and non‐immune cells remain poorly understood. Here, we show that MCs accumulate locally in skin lesions of patients with cutaneous candidiasis. In mouse models, MC‐deficient Kit ^{W‐sh/W‐sh} 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.