Hyperglycemia-induced P300/CBP acetyltransferase drives ZEB2-mediated proinflammatory macrophages and delays wound healing
Soumyajit Roy, Debarun Patra, Palla Ramprasad, Shivam Sharma, Parul Katiyar, Ashvind Bawa, Kanhaiya Singh, Kulbhushan Tikoo, Suman Dasgupta, Chandan K. Sen, Durba Pal
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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Research Article Dermatology Immunology Inflammation

Hyperglycemia-induced P300/CBP acetyltransferase drives ZEB2-mediated proinflammatory macrophages and delays wound healing

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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Figure 4

The suppression of Zeb2 ameliorated wound-healing complications in STZ-induced HFD mouse model.

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The suppression of Zeb2 ameliorated wound-healing complications in STZ-i...
(A) Gross photographs of wounds (n = 3 mice/group) during healing at different time points in different groups. (B) Healing curve showing wound size of original wound versus time in days (n = 3 mice/group). **P < 0.01, #P < 0.0001 by paired, 2-tailed Student’s t test. (C) Expression of ZEB2 and p-NF-κB protein assessed by Western blot in d3 and d7 mouse wound tissue. (D) Inflammatory status of the wound tissue assessed by the immunostaining for CD163 (green) and CD80 (red) in diabetic groups treated with Con ASO and Zeb2 ASO (250 μM/100 μL/wound) (scale bars: 500 μm, n = 3 mice/group). *P < 0.05, **P < 0.01 by paired, 2-tailed Student’s t test. (E) Reduced MLDTF expression upon Zeb2 inhibition in d10 murine wound tissue was assessed by relative mRNA expression. *P < 0.05, **P < 0.01 by paired, 2-tailed Student’s t test. Immunostaining for (F) ARG1, (G) IL-1β, and (H) iNOS was performed in d3 and d7 wound tissue to represent the inflammatory status upon Zeb2 inhibition at the wound site (scale bars: 500 μm, n = 3 mice/group). **P < 0.01 by paired, 2-tailed Student’s t test. Representative immunostaining images for (I) CD31 in d7, (J) αSMA in d7 and d10, and (K) CK14 in d10 mouse wound tissue for neoangiogenesis, remodeling, and reepithelialization status in the wound tissue upon Zeb2 inhibition (scale bars: 200 μm, n = 3 mice/group). **P < 0.01 by paired, 2-tailed Student’s t test. Data are expressed as mean ± standard deviation. NS, not significant; SD, standard diet; HFD, high-fat diet.