IL-24 regulates corneal inflammation and fibrosis in fungal keratitis via the caspase-11/gasdermin D pathway

Abstract

Background

This study aimed to investigate the role of interleukin-24 (IL-24) in the inflammatory response and repair of corneal damage caused by fungal keratitis (FK).

Methods

Mouse model was infected with Aspergillus fumigatus (A. fumigatus) to induce FK. An in vitro model was established by stimulating THP-1 cells and human corneal epithelial cells (HCECs) with A. fumigatus spores. IL-24 expression was inhibited by small interfering RNA (siRNA). The production and role of IL-24 in FK were evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence, clinical scoring, anterior segment optical coherence tomography (OCT), hematoxylin and eosin (HE) staining, confocal corneal microscopy, and myeloperoxidase (MPO) assays.

Results

IL-24 expression was increased in mouse models of FK, fungal-stimulated THP-1 macrophages, and HCECs compared to controls. Compared to controls, siRNA inhibition of IL-24 reduced the inflammatory response, corneal edema, and neutrophil and macrophage recruitment within the corneal stroma. In A. fumigatus-infected keratitis, IL-24 production was induced by hypoxia-inducible factor-1α (HIF-1α). Tumor necrosis factor-α (TNF-α), IL-6, and IL-10 were inflammatory factors regulated by IL-24, which played a role in pyroptosis via the caspase-11/gasdermin D (GSDMD) pathway. Inhibition of IL-24 attenuated corneal neovascularization and fibrosis during long-term FK in mice.

Conclusions

This study demonstrated the important role of IL-24 in corneal antifungal immunity. In A. fumigatus-infected keratitis, IL-24 might be crucial for the recruitment of inflammatory cells, induction of cellular pyroptosis, and production of inflammatory cytokines. Furthermore, IL-24 is also involved in the development of fibrosis during corneal repair.