Non‐immune and immune functions of interleukin‐36γ suppress epithelial repair at the ocular surface

Abstract

Regulation of innate inflammation is critical for maintaining tissue homeostasis and barrier function, especially in those interfacing the external environments such as the skin and cornea. Expression of pro‐inflammatory cytokines by injured tissues has been shown to exacerbate the inflammatory cascade, causing tissue damage. Interleukin 36, a subfamily of the IL‐1 superfamily, consists of three pro‐inflammatory agonists—IL36α, IL36β, and IL36γ and an IL36 receptor antagonist (IL36Ra). The current investigation, for the first time, reports that IL36γ is the primary agonist expressed by the corneal epithelium, which is significantly upregulated following corneal injury. The function of IL36γ on non‐immune cells, in addition to innate inflammatory cells, in regulating tissue homeostasis has not been well investigated. Using a loss‐of‐function approach via neutralizing antibody treatment, our data demonstrate that blocking endogenously expressed IL36γ in epithelial cells promotes rapid re‐epithelialization in in vitro wound closure assay. Finally, by utilizing a naturally occurring antagonist IL36Ra in a well‐established murine model of ocular injury, our study demonstrates that inhibition of IL36γ accelerates epithelial regeneration and suppresses tissue inflammation. Given rapid wound healing is critical for re‐establishing normal tissue structure and function, our investigation on the function of IL36γ provides evidence for the development of novel IL36γ‐targeting strategies to promote tissue repair.

Mesenchymal Stromal Cells Suppress T-Cell-Mediated Delayed-Type Hypersensitivity via ALCAM-CD6 Interaction

“…Pinnae thickness was measured from the epithelium to the cartilage (chondrocytes) using NIH ImageJ (version 1.34s) software. 23 …”

Mesenchymal stromal cells protect tissues from Th1 immune responses via IL‐11 secretion

“…Tissue cross‐sections were analyzed under a brightfield microscope (Leica DM750). Pinnae thickness was measured from the epithelium to the cartilage (chondrocytes) using NIH ImageJ (version 1.53 s) software 21,22 …”

Interleukin-11 Suppresses Ocular Surface Inflammation and Accelerates Wound Healing

“…One microliter of 1% sodium fluorescein dye (Sigma-Aldrich, St. Louis, MO, USA) was applied to the injured ocular surface, and positive staining was evaluated under cobalt blue light on the slit-lamp biomicroscope, as described previously. 16 CFS assessment was performed immediately following injury (day 0) and on alternate days thereafter until day 6 postinjury. Captured slit-lamp micrographs were analyzed to calculate the area of epithelial defect using ImageJ, version 1.5.3 (National Institutes of Health, Bethesda, MD, USA).…”

“…Sample sizes were estimated based on previous experimental studies on corneal injury and inflammation. 16 , 24 , 25 …”