Department of Anesthesiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China.
Clin Hemorheol Microcirc. 2023;85(1):13-30. doi: 10.3233/CH-221624.
Polymorphonuclear neutrophils (PMNs) exert significant roles in septic acute lung injury (ALI). Accumulating evidence suggests that PMN-derived exosomes (PMN-exo) are a novel subcellular entity that is the fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-exo in septic ALI and the underlying mechanisms remain unclear. Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in septic ALI, was used to induce PMN activation in vitro. Using an in vitro co-culture system, the rat alveolar macrophage cell line NR8383 was co-cultured with TNF-α-stimulated PMN-released exosomes (TNF-α-exo) to further confirm the results of the in vitro studies and explore the underlying mechanisms involved. A septic lung injury model was established by cecal ligation and puncture surgery, and PMN-exo were injected into septic mice through the tail vein, and then lung injury, inflammatory release, macrophage polarization, and apoptosis were examined. The results reported that TNF-α-exo promoted the activation of M1 macrophages after i.p. injection in vivo or co-culture in vitro. Furthermore, TNF-α-exo affected alveolar macrophage polarization by delivering HCG18. Mechanistic studies indicated that HCG18 mediated the function of TNF-α-exo by targeting IL-32 in macrophages. In addition, tail vein injection of si-HCG18 in septic mice significantly reduced TNF-α-exo-induced M1 macrophage activation and lung macrophage death, as well as histological lesions. In conclusion, TNF-α-exo-loaded HCG18 contributes to septic ALI by regulating macrophage polarization. These findings may provide new insights into novel mechanisms of PMN-macrophage polarization interactions in septic ALI and may provide new therapeutic strategies for patients with sepsis.
多形核粒细胞（PMN）在脓毒症性急性肺损伤（ALI）中发挥重要作用。越来越多的证据表明，PMN 衍生的外泌体（PMN-exo）是一种新型的亚细胞实体，是 PMN 驱动的炎症和组织损伤之间的基本联系。然而，PMN-exo 在脓毒症性 ALI 中的作用及其潜在机制尚不清楚。肿瘤坏死因子-α（TNF-α）是脓毒症性 ALI 中固有免疫的关键调节剂，用于体外诱导 PMN 活化。使用体外共培养系统，将大鼠肺泡巨噬细胞系 NR8383 与 TNF-α 刺激的 PMN 释放的外泌体（TNF-α-exo）共培养，以进一步证实体外研究的结果，并探讨涉及的潜在机制。通过盲肠结扎和穿孔手术建立脓毒症性肺损伤模型，通过尾静脉将 PMN-exo 注入脓毒症小鼠体内，然后检查肺损伤、炎症释放、巨噬细胞极化和细胞凋亡。研究结果表明，TNF-α-exo 促进了体内腹腔注射或体外共培养后 M1 巨噬细胞的活化。此外，TNF-α-exo 通过向肺泡巨噬细胞传递 HCG18 来影响肺泡巨噬细胞的极化。机制研究表明，HCG18 通过在巨噬细胞中靶向 IL-32 来介导 TNF-α-exo 的功能。此外，在脓毒症小鼠中尾静脉注射 si-HCG18 可显著减少 TNF-α-exo 诱导的 M1 巨噬细胞活化和肺巨噬细胞死亡以及组织学损伤。总之，载有 HCG18 的 TNF-α-exo 通过调节巨噬细胞极化促进脓毒症性 ALI。这些发现可能为脓毒症性 ALI 中 PMN-巨噬细胞极化相互作用的新机制提供新的见解，并为脓毒症患者提供新的治疗策略。
