Journal
OCULAR SURFACE
Volume 18, Issue 4, Pages 633-640Publisher
ELSEVIER
DOI: 10.1016/j.jtos.2020.06.006
Keywords
Cornea; Ocular surface; Injury; Inflammation; Mast cells; Neutrophils
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Purpose: Neutrophils play a critical role in defending against threats such as microbial infection, yet their activation during innate immune response incites collateral damage to healthy tissues. We have previously shown that corneal injury induces mast cells to express the neutrophil chemoattractant CXCL2. Here we delineate the mechanism of injury-induced, non-IgE-mediated mast cell activation at the ocular surface. Methods: Corneal injury was induced by mechanical removal of the epithelium and anterior stroma in mast cell deficient (cKit(W-sh)) and C57BL/6 mice using Algerbrush II. Corneas were analyzed for frequncies of total CD45(+) inflammatory cells, CD11b(+)Ly6G(+) neutrophils, and cKit(+)FceR1(+) mast cells using flow cytometry. Mast cells were stimulated with different inflammatory factors known to increase during corneal injury (IL-33, IL-1 beta, IL-36 gamma, IL-6, SDF1 alpha and Substance P) and assessed for the secretion of beta-hexosaminidase, tryptase and CXCL2 using ELISA. IL-33 neutralizing antibody (1 mg/ml) was administered locally for mast cell inhibition in vivo. Results: Mast cell deficient mice failed to recruit early neutrophils to the injured corneas. IL-33 stimulation upregulated CXCL2 secretion by mast cells. Corneal injury resulted in amplified expression of IL-33 at the cornea and epithelium was identified as its primary source. Topical neutralization of IL-33 at the ocular surface inhibited mast cell activation, limited neutrophil infiltration, and reduced corneal inflammatory haze, normalizing tissue architecture following ocular injury. Conclusions: These data implicate IL-33 in mast cell activation and early neutrophil recruitment in non-allergic inflammation, suggesting IL-33 as a potential therapeutic target in inflammatory disorders of the ocular surface.
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