Abstract
Chronic hyperglycemia changes the expression of various transcription factors and mRNA transcripts that impair cellular functionality and delay wound healing. Zinc finger E-box–binding homeobox 2 (ZEB2), a key transcription factor, maintains tissue-specific macrophage identities; however, its role in regulating macrophage polarization during wound healing under hyperglycemic conditions remains unclear. Here, we found that persistent hyperglycemia increases ZEB2 expression in wound macrophages via histone acetylation, contributing to chronic inflammation and delayed wound healing. Exposure to high glucose levels activated P300/CBP, a transcriptional coactivator involved in histone acetylation, which enhanced ZEB2 expression in wound macrophages. The forced expression of ZEB2 shifted macrophage polarity toward a proinflammatory state by upregulating myeloid lineage–directed transcription factors. Conversely, silencing Zeb2 at the wound site reduced hyperglycemia-induced macrophage inflammation. Topical application of C646, an inhibitor of P300, at the wound edges of streptozotocin-induced high-fat diet–fed diabetic mice significantly decreased ZEB2 expression, reduced inflammation, and accelerated wound healing. Therefore, targeted inhibition of P300 represents a promising therapeutic strategy for improving diabetic wound healing by modulating ZEB2-driven inflammation in wound macrophages.
Authors
Soumyajit Roy, Debarun Patra, Palla Ramprasad, Shivam Sharma, Parul Katiyar, Ashvind Bawa, Kanhaiya Singh, Kulbhushan Tikoo, Suman Dasgupta, Chandan K. Sen, Durba Pal
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