Recombinant IL-22 promotes protection in a murine model of Aspergillus flavus keratitis and mediates host immune responses in human corneal epithelial cells

Abstract

Aspergillus flavus is a leading cause of corneal infections in India and worldwide, resulting in severe visual impairment. We studied the host immune response towards A. flavus in immortalised human corneal epithelial cells (HCEC) and found increased expression of Toll-like receptors, antimicrobial peptides and proinflammatory cytokines like IL-6 and IL-8. Differential expressions of antimicrobial peptides were determined in corneal scrapings from A. flavus keratitis patients with significantly increased expression of LL-37, S100A12 and RNase 7. Increased levels of IL-22 expression were observed both in patients with A. flavus keratitis and in experimental mice model of corneal infections along with IL-17, IL-23 and IL-18. IL-22 is an important mediator of inflammation during microbial infections, and acts primarily on fibroblasts and epithelial cells. We observed constitutive expression of IL-22 receptors in HCEC, and IL-22 mediated activation of NF-κB, MAPK pathways and STAT3, along with increased expression of antimicrobial peptides in these cells. IL-22 also efficiently lessened cell deaths in corneal epithelial cells during A. flavus infection in vitro. Furthermore, recombinant IL-22 reduced fungal burden and corneal opacity in an experimental murine model of A. flavus keratitis.