November 30, 2025Open Access

Candida albicans Enhances Protease Activity and Activates MyD88 ‐Dependent IL ‐1β Production in Human Keratinocytes

Key Points

Candida albicans enhances IL-1β secretion and proteolytic activity in keratinocytes, revealing its role in skin inflammation.
The study identifies that increased cytokine secretion leads to impaired epidermal barrier function in keratinocytes.
Utilizing CRISPR/Cas9 technology, signaling pathways involved in the Candida-induced response were dissected.
These findings suggest a potential link between skin resident fungi and immune responses in atopic dermatitis.

Abstract

ABSTRACT Background Atopic dermatitis (AD) is a common chronic skin disorder characterised by a highly inflamed local environment and elevated epidermal proteolytic activity. Changes in the skin mycobiome have been observed in this disease, specifically Candida albicans colonization positively correlating with AD severity, yet the mechanisms by which this fungus contributes to disease features remain elusive. Objectives This study aimed to elucidate how C. albicans can influence AD pathogenesis through its influence on keratinocyte (KC) proteolytic activity, inflammatory cytokine secretion and epidermal barrier integrity, as well as define the signaling pathways mediating these effects. Methods Immortalized human KC were co‐cultured with C. albicans and changes in KC protease expression and activity, along with the secretion of the pro‐inflammatory cytokine IL‐1β were assessed. Additionally, the impact of IL‐1β on KC barrier formation was determined using transepithelial electrical resistance. To identify signalling pathways mediating Candida ‐induced phenotypes, CRISPR/Cas9 was used to establish cell lines deficient in myeloid differentiation primary response protein 88 (MyD88) or matrix metalloprotease‐9 (MMP‐9). Results C. albicans induced proteolytic activity from KC through fungal secreted aspartyl proteases (Sap4‐6) and promoted IL‐1β secretion via MyD88 signalling. This response increased expression and activation of host MMP‐9 and led to impaired barrier function. Genetic deletion of either MYD88 or MMP9 restored barrier function in IL‐1β treated cells, suggesting MMP‐9 serves as a downstream effector of IL‐1β/MyD88 signalling. Conclusion These findings establish a mechanistic link between skin resident fungi and epidermal barrier dysfunction. We demonstrate a pathway linking fungal colonization to innate immune responses by skin cells, providing insight into how the commensal fungus C. albicans may contribute to AD pathogenesis.

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