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

## TL;DR

This study shows how the fungus Candida albicans worsens skin inflammation and barrier issues in atopic dermatitis by triggering immune responses and protease activity in skin cells.

## Contribution

The study identifies a novel MyD88-dependent pathway linking Candida albicans to IL-1β secretion and epidermal barrier dysfunction in atopic dermatitis.

## Key findings

- Candida albicans increases proteolytic activity in keratinocytes via fungal aspartyl proteases.
- Candida-induced IL-1β secretion occurs through MyD88 signaling, leading to impaired skin barrier function.
- Genetic deletion of MyD88 or MMP-9 restores barrier function, showing their role in disease progression.

## Abstract

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.

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.

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).

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.

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.