PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4
PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4
复制标题
通过结合 eIF3I 触发 PD-L1 通过调节 IRS4 有助于改善糖尿病相关的伤口愈合缺陷
DOI：
10.1016/j.jid.2021.06.028
复制
发表时间：
2022
影响因子：
6.5
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Kuai L;Xiang YW;Chen QL;Ru Y;Yin SY;Li W;Jiang JS;Luo Y;Song JK;Lu B;Luo Y;Li B
持续的慢性炎症和延迟的上皮化导致糖尿病溃疡(DU)的愈合停滞。PD-L1在修复缺陷中具有抗炎和增殖活性，但其在DU发病机制中的作用尚不清楚。在DU组织中，PD-L1水平较低，外源性PD-L1在愈合过程中通过促进再上皮化和减轻持续的炎症而发挥治疗作用，这是导致伤口延迟闭合的原因之一。我们用转录谱检测PD-L1下游的效应物，并用免疫沉淀结合质谱学和免疫共沉淀分析筛选相互作用的蛋白。体内和体外检测eIF3I-PD-L1-Irs4轴的生物学功能。最后，我们通过免疫组织化学染色验证了eIF3I、PD-L1和Irs4在人临床标本中的表达水平。机制上，PD-L1与eIF3I结合，通过下调Irs4促进糖尿病皮肤创面愈合。这些发现表明eIF3I-PD-L1-Irs4轴参与了创面愈合缺陷的形成，可以作为DU潜在的治疗靶点。
Persistent chronic inflammation and delayed epithelialization lead to stalled healing in diabetic ulcers (DUs). PD-L1 shows anti-inflammatory and proliferative activities in healing defects, whereas its function in DU pathogenesis remains unknown. Lower levels of PD-L1 were found in DU tissues, and exogenous PD-L1 has therapeutic effects in the healing process by accelerating re-epithelialization and attenuating prolonged inflammation, which contributed to the delayed wound closure. We detected the downstream effectors of PD-L1 using transcriptional profiles and screened the interacting proteins using immunoprecipitation in combination with mass spectrometry and coimmunoprecipitation assays. The biological functions of eIF3I‒PD-L1‒IRS4 axis were tested both in vivo and in vitro. Finally, we validated the expression levels of eIF3I, PD-L1, and IRS4 in DU tissues from human clinical samples by immunohistochemistry staining. Mechanistically, PD-L1 binds to eIF3I and promotes cutaneous diabetic wound healing by downregulating IRS4. These findings identify that the eIF3I‒PD-L1‒IRS4 axis contributes to wound healing defects, which can serve as a potential therapeutic target in DUs.