Tissue Inhibitor of Metalloproteinase 2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) modulate extracellular matrix remodeling for maintaining homeostasis and promoting cell migration and proliferation. Pathologic 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 cells under homeostatic and inflammatory milieus was profiled to examine their contribution to the healing of injured corneal epithelia. Transcriptionally, TIMP2 was highly expressed in human corneal epithelial cells when stimulated with 100 ng/mL IL1B or scratch wounded. Unlike TIMP1, recombinant TIMP2 (rTIMP2) significantly promoted epithelial cell wound closure compared with untreated and TIMP2-neutralizing conditions. At 12 hours, the Ki-67⁺ cells significantly increased threefold in number compared with untreated cells, suggesting that rTIMP2 is associated with cell proliferation. Furthermore, rTIMP2 treatment significantly suppressed inflammatory cytokine expression (IL1B, IL6, IL8, and TNFA) and injury-induced matrix metalloproteinases (MMP1, MMP2, MMP3, MMP9, MMP10, and MMP13). Topical treatment of injured mouse cornea with 0.1 mg/mL rTIMP2 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 TIMP2 promotes faster wound healing by suppressing injury-induced inflammation and MMP expression, suggesting a potential therapeutic target for corneal wound management.