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

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.