Tissue Inhibitor of Metalloproteinase 2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells
Olufemi S. Folorunso, Nishant R. Sinha, Aastha Singh, Lei Xi, Vinay K. Pulimamidi, WonKyung J. Cho, Sharad K. Mittal, Sunil K. Chauhan
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引用次数: 0
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.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.