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KLF4 Promotes Diabetic Chronic Wound Healing by Suppressing Th17 Cell Differentiation in an MDSC-Dependent Manner
Journal of Diabetes Research ( IF 4.3 ) Pub Date : 2021-09-15 , DOI: 10.1155/2021/7945117
Xiong Yang 1 , Bryan J Mathis 2 , Yu Huang 1 , Wencheng Li 1 , Ying Shi 1
Affiliation  

Objectives. Diabetic wound inflammation deficiencies lead to ulcer development and eventual amputation and disability. Our previous research demonstrates that myeloid-derived suppressor cells (MDSCs) accumulate during inflammation and promote chronic wound healing via the regulation of Kruppel-like factor 4 (KLF4). In this study, we aimed to investigate the potential roles of MDSCs and KLF4 in diabetic wound healing. Methods. An ob/ob mouse pressure ulcer (PU) model was used to evaluate the process of wound healing. The expression levels of KLF4 and IL-17A were measured by real-time PCR, and the population of MDSCs and Th17 cells was measured by flow cytometry. The levels of cytokines were determined by an immunosuppression assay. Results. KLF4 deficiency in the diabetic PU model resulted in decreased accumulation of MDSCs, increased expansion of Th17 cells, and significantly delayed wound healing. Conversely, KLF4 activation by APTO-253 accelerated wound healing accompanied by increased MDSC populations and decreased numbers of Th17 cells. MDSCs have been proven to mediate Th17 differentiation via cytokines, and our in vitro data showed that elevated KLF4 expression in MDSCs resulted in reduced Th17 cell numbers and, thus, decreased levels of cytokines indispensable for Th17 differentiation. Conclusions. Our study revealed a previously unreported function of KLF4-regulated MDSCs in diabetic wound healing and identified APTO-253 as a potential agent to improve the healing of pressure ulcers.

中文翻译:

KLF4通过以MDSC依赖性方式抑制Th17细胞分化促进糖尿病慢性伤口愈合

目标。糖尿病伤口炎症缺陷导致溃疡发展和最终截肢和残疾。我们之前的研究表明,髓源性抑制细胞 (MDSCs) 在炎症过程中积累,并通过调节 Kruppel 样因子 4 (KLF4) 促进慢性伤口愈合。在这项研究中,我们旨在研究 MDSC 和 KLF4 在糖尿病伤口愈合中的潜在作用。方法。ob/ob 小鼠压力性溃疡 (PU) 模型用于评估伤口愈合过程。实时荧光定量PCR检测KLF4和IL-17A的表达水平,流式细胞仪检测MDSCs和Th17细胞的数量。通过免疫抑制测定确定细胞因子的水平。结果. 糖尿病 PU 模型中的 KLF4 缺乏导致 MDSC 的积累减少,Th17 细胞的扩增增加,并显着延迟伤口愈合。相反,APTO-253 对 KLF4 的激活加速了伤口愈合,同时 MDSC 数量增加,Th17 细胞数量减少。MDSCs 已被证明通过细胞因子介导 Th17 分化,我们的体外数据显示,MDSCs 中 KLF4 表达升高导致 Th17 细胞数量减少,因此 Th17 分化所必需的细胞因子水平降低。结论。我们的研究揭示了 KLF4 调节的 MDSC 在糖尿病伤口愈合中的先前未报道的功能,并将 APTO-253 确定为改善压疮愈合的潜在药物。
更新日期:2021-09-15
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