Keratinocyte-mast cell NF-κB2/CXCL2/IL-6 loop boosts skin antifungal defense against C. albicans

Cutaneous Candida albicans (C. albicans) infections are common, ranging from superficial skin candidiasis to more severe systemic manifestations in immunocompromised individuals. The skin acts as a crucial barrier, but the precise cellular and molecular mechanisms orchestrating its defense against fungal pathogens are not fully understood. While mast cells (MCs) are recognized as key innate immune sentinels, their specific contribution to antifungal immunity, particularly in synergy with non-immune cells like keratinocytes (KCs), has remained an area of active investigation. Understanding these interactions could reveal novel therapeutic targets for persistent or recurrent fungal infections.

Researchers investigated the intricate interplay between keratinocytes and mast cells in the context of C. albicans infection. They utilized in vitro cellular models to delineate the signaling pathways activated in response to fungal challenge, focusing on the non-canonical NF-κB2 pathway. The study also explored the release of specific chemokines and cytokines, and their reciprocal effects between the two cell types. Furthermore, the team assessed the impact of topical recombinant IL-6 on keratinocyte-mediated antifungal activity, likely employing an in vivo cutaneous infection model, though specific model details, doses, or sample sizes were not provided in the abstract.

The study uncovered a critical amplification loop between keratinocytes and mast cells that significantly enhances antifungal defense. In response to C. albicans, keratinocytes activate the non-canonical NF-κB (NF-κB2) pathway. This activation leads to the release of the chemokine CXCL2 from keratinocytes. CXCL2 then signals through its receptor, CXCR2, which is expressed on mast cells, triggering further downstream effects. This CXCL2-CXCR2 interaction on mast cells robustly promotes the secretion of IL-6, a potent pro-inflammatory cytokine.

This establishes a novel NF-κB2-CXCL2-IL-6 amplification loop, where keratinocytes initiate the response, and mast cells amplify it through IL-6 secretion, creating a positive feedback mechanism between the two cell types.

Crucially, the researchers demonstrated that topical recombinant IL-6 directly enhanced the antifungal activity mediated by keratinocytes, suggesting a direct role for IL-6 in boosting the skin's ability to combat C. albicans infection.