Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China.
College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, P.R. China.
Int J Biol Sci. 2022 Jul 4;18(11):4388-4399. doi: 10.7150/ijbs.69890. eCollection 2022.
Chronic non-healing wounds fail to progress beyond the inflammatory phase, characterized by a disorder of inflammation resolution. PD-1/PD-L1, a major co-inhibitory checkpoint signaling, plays critical roles in tumor immune surveillance and the occurrence of inflammatory or autoimmune diseases, but its roles in wound healing remains unclear. Here, we described a novel function of PD-L1 in fibroblast-like cells as a positive regulator of wound healing. PD-L1 dynamically expressed on the fibroblast-like cells in the granulation tissue during wound healing to form a wound immunosuppressive microenvironment, modulate macrophages polarization from M1-type to M2-type, and initiates resolution of inflammation, finally accelerate wound healing. Loss of PD-L1 delayed wound healing, especially in mice with LPS-induced severe inflammation. Furthermore, the mainly regulatory mechanism is that combination of FGF-2 and TGF-β1 promotes PD-L1 translation in fibroblasts through enhancing the eIF4E availability regulated by both PI3K-AKT-mTOR-4EBP1 and p38-ERK-MNK signaling pathways. Our results reveal the positive role of PD-L1 in wound healing, and provide a new strategy for the treatment of chronic wounds.
慢性非愈合性伤口无法进入炎症消退期，其特征是炎症消退紊乱。PD-1/PD-L1 是主要的共抑制检查点信号，在肿瘤免疫监视和炎症或自身免疫性疾病的发生中起着关键作用，但它在伤口愈合中的作用尚不清楚。在这里，我们描述了 PD-L1 在成纤维细胞样细胞中的一个新功能，作为伤口愈合的正调节剂。PD-L1 在伤口愈合过程中肉芽组织中的成纤维细胞样细胞上动态表达，形成伤口免疫抑制微环境，调节巨噬细胞从 M1 型向 M2 型极化，并启动炎症消退，最终加速伤口愈合。PD-L1 的缺失会延迟伤口愈合，尤其是在 LPS 诱导的严重炎症的小鼠中。此外，主要的调节机制是，FGF-2 和 TGF-β1 的结合通过增强 PI3K-AKT-mTOR-4EBP1 和 p38-ERK-MNK 信号通路调节的 eIF4E 可用性，促进成纤维细胞中 PD-L1 的翻译。我们的结果揭示了 PD-L1 在伤口愈合中的积极作用，并为慢性伤口的治疗提供了一种新策略。
