Staphylococcus aureus-derived virulent phenol-soluble modulin a triggers alarmin release to drive IL-36-dependent corneal inflammation

Methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients with keratitis produces substantial amounts of phenol-soluble modulin a (PSMa). However, the role of PSMa in S. aureus keratitis remains unclear. We observed that PSMa-producing and PSMa-deficient strains could infect the cornea in our experimental mouse keratitis model; however, only the PSMa-producing strain delayed epithelial wound healing and induced stromal inflammation. PSMa induced damage to the epithelium, the release of alarmins IL-1a and IL-36a, and the expression of inflammatory chemokines by resident corneal cells in the mouse corneal organ culture. The IL-36 (but not IL-1) receptor antagonist attenuated mouse keratitis induced by PSMa-containing bacterial culture supernatants, as well as by infection with PSMa-producing S. aureus, suggesting that the corneal inflammations were dependent on IL-36. Recombinant PSMa elicited IL-36-dependent corneal inflammation in mice. Thus, PSMa and the subsequently released IL-36 are critical factors triggering inflammation during S. aureus keratitis. (c) 2023 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.