Interleukin-36 Receptor Signaling Attenuates Epithelial Wound Healing in C57BL/6 Mouse Corneas

The IL-36 cytokines are known to play various roles in mediating the immune and inflammatory response to tissue injury in a context-dependent manner. This study investigated the role of IL-36R signaling in mediating epithelial wound healing in normal (NL) and diabetic (DM) C57BL/6 mouse corneas. The rate of epithelial wound closure was significantly accelerated in IL-36 receptor-deficient (IL-36R(-/-)) compared to wild-type (WT) mice. Wounding increased IL-36 & alpha; and -36 & gamma; but repressed IL-36R antagonist (IL-36Ra) expression in B6 mouse corneal epithelial cells. The wound-induced proinflammatory cytokines CXCL1 and CXCL2 were dampened, while the antimicrobial peptides (AMPs) S100A8 and A9 were augmented in IL-36R(-/-) mouse corneas. Intriguingly, the expression of AMP LCN2 was augmented at the mRNA level. LCN2 deficiency resulted in an acceleration of epithelial wound healing. IL-36R deficiency also greatly increased the healing rate of the corneal epithelial wound in DM mice. IL-36R deficiency also suppressed IL-1 & beta;, IL-1Ra, and ICAM expression in unwounded-DM mice and wounded NL corneas. Opposing IL-1 & beta; and ICAM, the expression of IL-Ra in DM corneas of IL-36R(-/-) mice was augmented. The presence of recombinant IL-1Ra and IL-36Ra accelerated epithelial wound closure in T1DM corneas of B6 mice. Our study revealed an unprecedented role of IL-36R signaling in controlling corneal epithelial wound healing in normal (NL) and diabetic (DM) mice. Our data suggest that IL-36Ra, similar to IL-1Ra, might be a therapeutic reagent for improving wound healing and reducing wound-associated ulceration, particularly in the cornea and potentially in the skin of DM patients.

Automated summary

IL-36 cytokines have different roles in mediating immune and inflammatory response. This study showed that IL-36R signaling plays a role in corneal epithelial wound healing and IL-36R deficiency accelerates the healing process. The expression of certain proinflammatory cytokines and antimicrobial peptides were affected by IL-36R deficiency. IL-36Ra could be a potential therapeutic agent for wound healing and ulcer reduction.