Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan.
Redox Biol. 2021 Oct;46:102086. doi: 10.1016/j.redox.2021.102086. Epub 2021 Jul 28.
After cardiopulmonary bypass (CPB), the occurrence of systemic inflammatory response is often accompanied by a persistent compensatory anti-inflammatory response syndrome that can lead to a compromised immune competence termed immunoparalysis, rendering the patients susceptible to infections which is a leading complication following cardiac surgery. However, the underlying mechanisms of CPB-elicited immunoparalysis remain obscure. In this study we showed that peroxiredoxin 1 (Prdx1), a putative cytosolic antioxidant, was released immediately after CPB in a cohort of pediatric patients receiving congenital cardiac surgery. This increased Prdx1 was correlated to a reduced human leukocyte antigen-DR expression and an elevated interleukin-10 (IL-10) production, as well as a hypo-responsiveness of macrophages to endotoxin and a higher incidence of nosocomial infection. We demonstrated that substitution of Ser for Cys prevented Prdx1 from oligomerization and subsequent binding and internalization to macrophages. These effects mitigated Prdx1-induced IL-10 induction and endotoxin tolerance. Furthermore, after engagement with toll-like receptor (TLR) 4, clathrin-dependent endocytosis is crucial for Prdx1 to elicit IL-10 production in phagocytes. Congruently, inhibition of Prdx1/TLR4 endocytosis in phagocytes reversed the Prdx1/IL-10-mediated hypo-responsiveness to endotoxin. Our findings unveiled the possible mechanisms by which Prdx1 undertakes to cause immunoparalysis, and targeting endocytosis of Prdx1 could be a novel therapeutic approach for postoperative infections associated with CPB.
体外循环（CPB）后，全身炎症反应的发生常伴有持续的代偿性抗炎反应综合征，导致免疫功能受损，称为免疫麻痹，使患者易发生感染，这是心脏手术后的主要并发症。然而，CPB 引起的免疫麻痹的潜在机制仍不清楚。在这项研究中，我们发现在接受先天性心脏手术的儿科患者群体中，过氧化物酶 1（Prdx1），一种假定的细胞溶质抗氧化剂，在 CPB 后立即释放。这种增加的 Prdx1 与人类白细胞抗原-DR 表达降低和白细胞介素-10（IL-10）产生增加以及巨噬细胞对内毒素的反应性降低和医院获得性感染的发生率增加相关。我们证明，丝氨酸取代半胱氨酸可防止 Prdx1 寡聚化以及随后与巨噬细胞结合和内化。这些作用减轻了 Prdx1 诱导的 IL-10 诱导和内毒素耐受。此外，在与 toll 样受体（TLR）4 结合后，网格蛋白依赖性内吞作用对于 Prdx1 在吞噬细胞中引发 IL-10 产生至关重要。一致地，抑制吞噬细胞中 Prdx1/TLR4 的内吞作用可逆转 Prdx1/IL-10 介导的对内毒素的低反应性。我们的研究结果揭示了 Prdx1 引起免疫麻痹的可能机制，靶向 Prdx1 的内吞作用可能是与 CPB 相关的术后感染的一种新的治疗方法。
