Department of Medical Science, Kosin University College of Medicine, Busan, Republic of Korea.
Department of Chemical Engineering, Pukyong National University, Busan, Republic of Korea.
Elife. 2024 Oct 8;13:RP95285. doi: 10.7554/eLife.95285.
The gram-negative bacterium lipopolysaccharide (LPS) is frequently administered to generate models of systemic inflammation. However, there are several side effects and no effective treatment for LPS-induced systemic inflammation. PEGylated PDZ peptide based on zonula occludens-1 (ZO-1) was analyzed for its effects on systemic inflammation induced by LPS. PDZ peptide administration led to the restoration of tissue injuries (kidney, liver, and lung) and prevented alterations in biochemical plasma markers. The production of pro-inflammatory cytokines was significantly decreased in the plasma and lung BALF in the PDZ-administered mice. Flow cytometry analysis revealed the PDZ peptide significantly inhibited inflammation, mainly by decreasing the population of M1 macrophages, and neutrophils (immature and mature), and increasing M2 macrophages. Using RNA sequencing analysis, the expression levels of the NF-κB-related proteins were lower in PDZ-treated cells than in LPS-treated cells. In addition, wild-type PDZ peptide significantly increased mitochondrial membrane integrity and decreased LPS-induced mitochondria fission. Interestingly, PDZ peptide dramatically could reduce LPS-induced NF-κB signaling, ROS production, and the expression of M1 macrophage marker proteins, but increased the expression of M2 macrophage marker proteins. These results indicated that PEGylated PDZ peptide inhibits LPS-induced systemic inflammation, reducing tissue injuries and reestablishing homeostasis, and may be a therapeutic candidate against systemic inflammation.
革兰氏阴性菌脂多糖（LPS）常被用来产生全身炎症模型。然而，LPS 诱导的全身炎症有许多副作用，且没有有效的治疗方法。基于紧密连接蛋白-1（ZO-1）的聚乙二醇化 PDZ 肽被分析用于治疗 LPS 诱导的全身炎症。PDZ 肽给药导致组织损伤（肾脏、肝脏和肺部）的恢复，并防止生化血浆标志物的改变。PDZ 给药的小鼠血浆和肺 BALF 中促炎细胞因子的产生显著减少。流式细胞术分析显示，PDZ 肽主要通过减少 M1 巨噬细胞和中性粒细胞（幼稚和成熟）的数量，增加 M2 巨噬细胞，显著抑制炎症。使用 RNA 测序分析，与 LPS 处理的细胞相比，PDZ 处理的细胞中 NF-κB 相关蛋白的表达水平较低。此外，野生型 PDZ 肽显著增加了线粒体膜的完整性，并减少了 LPS 诱导的线粒体分裂。有趣的是，PDZ 肽可显著降低 LPS 诱导的 NF-κB 信号、ROS 产生和 M1 巨噬细胞标记蛋白的表达，但增加了 M2 巨噬细胞标记蛋白的表达。这些结果表明，聚乙二醇化 PDZ 肽抑制 LPS 诱导的全身炎症，减少组织损伤并重新建立体内平衡，可能是治疗全身炎症的候选药物。
