{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:06:27Z","timestamp":1784261187929,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NEI","award":["R01EY10869"],"award-info":[{"award-number":["R01EY10869"]}]},{"name":"NIH\/NEI","award":["EY17960"],"award-info":[{"award-number":["EY17960"]}]},{"name":"NIH\/NEI","award":["p30 EY004068"],"award-info":[{"award-number":["p30 EY004068"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2212\/\u2212) compared to wild-type (WT) mice. Wounding increased IL-36\u03b1 and -36\u03b3 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\u2212\/\u2212 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\u03b2, IL-1Ra, and ICAM expression in unwounded-DM mice and wounded NL corneas. Opposing IL-1\u03b2 and ICAM, the expression of IL-Ra in DM corneas of IL-36R\u2212\/\u2212 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.<\/jats:p>","DOI":"10.3390\/cells12121587","type":"journal-article","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T03:59:56Z","timestamp":1686196796000},"page":"1587","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Interleukin-36 Receptor Signaling Attenuates Epithelial Wound Healing in C57BL\/6 Mouse Corneas"],"prefix":"10.3390","volume":"12","author":[{"given":"Qi","family":"Chen","sequence":"first","affiliation":[{"name":"Departments of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0259-3316","authenticated-orcid":false,"given":"Nan","family":"Gao","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Shin","family":"Yu","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27540","DOI":"10.1073\/pnas.2004484117","article-title":"IL-36R signaling integrates innate and adaptive immune-mediated protection against enteropathogenic bacteria","volume":"117","author":"Ngo","year":"2020","journal-title":"Proc. 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