Kuai Le, Xiang Yan-Wei, Chen Qi-Long, Ru Yi, Yin Shuang-Yi, Li Wei, Jiang Jing-Si, Luo Ying, Song Jian-Kun, Lu Bing, Luo Yue, Li Bin
Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Invest Dermatol. 2022 Jan;142(1):220-231.e8. doi: 10.1016/j.jid.2021.06.028. Epub 2021 Jul 20.
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.
持续性慢性炎症和上皮化延迟导致糖尿病溃疡（DUs）愈合停滞。程序性死亡配体1（PD-L1）在愈合缺陷中显示出抗炎和增殖活性，但其在DU发病机制中的作用尚不清楚。在DU组织中发现PD-L1水平较低，外源性PD-L1通过加速再上皮化和减轻长期炎症在愈合过程中具有治疗作用，而长期炎症会导致伤口闭合延迟。我们使用转录谱检测了PD-L1的下游效应器，并结合质谱和免疫共沉淀分析，通过免疫沉淀筛选了相互作用蛋白。在体内和体外测试了真核翻译起始因子3I（eIF3I）-PD-L1-胰岛素受体底物4（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人临床样本中DU组织中eIF3I、PD-L1和IRS4的表达水平。从机制上讲，PD-L1与eIF3I结合，并通过下调IRS4促进皮肤糖尿病伤口愈合。这些发现表明，eIF3I-PD-L1-IRS4轴导致伤口愈合缺陷，这可能成为DU的潜在治疗靶点。
