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

## TL;DR

This study shows how a skin yeast interacts with bacteria to influence inflammation in skin cells under steroid treatment, offering new insights into acne and immune responses.

## Contribution

The study reveals a novel mechanism of fungal-bacterial crosstalk modulating glucocorticoid-primed TLR2 signaling in human skin.

## Key findings

- Malassezia restricta suppresses dexamethasone-enhanced TLR2 expression by Cutibacterium acnes in keratinocytes.
- M. restricta modulates TLR2 signaling via p38 MAPK activation and inhibition of NF-κB p65 nuclear translocation.
- Fungal-bacterial interactions shape host immune responses in steroid-treated skin, impacting acne pathogenesis.

## Abstract

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.