Fungal-Bacterial Crosstalk Modulates Glucocorticoid-Primed TLR2 Signaling in the Human Skin.

Cutibacterium acnes, a major skin commensal bacterium, induces inflammatory cytokine production in keratinocytes through Toll-like receptor 2 (TLR2) signaling and contributes to acne vulgaris pathogenesis. Although glucocorticoids, e.g., dexamethasone (Dex), exert anti-inflammatory effects in related treatments, prolonged glucocorticoid exposure paradoxically induces acneiform eruptions, a phenomenon referred to as steroid-induced acne. Moreover, how commensal fungi influence bacterial-driven inflammatory signaling under glucocorticoid treatment remains unclear. In this study, we investigated how the lipophilic skin yeast Malassezia restricta affects C. acnes-induced TLR2 expression under Dex treatment using normal human epidermal keratinocytes. We discovered that M. restricta selectively suppressed Dex-enhanced C. acnes-induced TLR2 expression both at the transcriptional level and cell surface. Mechanistically, M. restricta enhanced p38 MAPK phosphorylation and inhibited NF-κB p65 nuclear translocation, indicating context-dependent glucocorticoid-primed TLR2 signaling modulation rather than simple inhibition. These results demonstrate that M. restricta modulates bacterial-induced inflammatory responsiveness in keratinocytes under glucocorticoid exposure and highlight the importance of fungal-bacterial interactions in shaping host immune signaling in steroid-treated skin. Our study provides new insight into the mechanistic basis of steroid-induced acne and the polymicrobial regulation of cutaneous innate immunity.