TIMP-2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells.

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) modulate extracellular matrix (ECM) remodeling for maintaining homeostasis and promoting cell migration and proliferation. Pathological conditions can alter TIMP homeostasis and aggravate disease progression. The roles of TIMPs have been studied in tissue-related disorders; however, their contributions to tissue repair during corneal injury are undefined. Here, the TIMP expression in human corneal epithelial (HCLE) cells under homeostatic and inflammatory milieus was profiled to examine their contribution to the healing of injured cornea epithelia. Transcriptionally, TIMP-2 was highly expressed in HCLE when stimulated with 100 ng/mL IL-1β or scratch-wounded. Unlike TIMP-1, recombinant TIMP-2 (rTIMP-2) significantly promoted epithelial cell wound closure compared to untreated and TIMP-2-neutralizing conditions. At 12 hours, the Ki-67+ cells significantly increased 3-fold compared to untreated cells, suggesting that rTIMP-2 is associated with cell proliferation. Furthermore, rTIMP-2 treatment significantly suppressed inflammatory cytokine expression (IL-1β, IL-6, IL-8, and TNFα) and injury-induced matrix metalloproteinases (MMP-1, -2, -3, -9, -10, and -13). Topical treatment of injured mouse cornea with 0.1 mg/mL rTIMP-2 significantly promoted corneal re-epithelialization and improved tissue integrity. The treatment suppressed the expression of inflammatory cytokines and MMPs, as well as the infiltration of neutrophils at the injury site. These findings indicate that TIMP-2 promotes faster wound healing by suppressing injury-induced inflammation and MMP expression, suggesting a potential therapeutic target for corneal wound management.