Liu, Chia-HsiungChia-HsiungLiuHuang, Zheng-HuaZheng-HuaHuangSHU-CHIEN HUANGTZUU-SHUH JOU2021-08-192021-08-1920212213-2317https://scholars.lib.ntu.edu.tw/handle/123456789/578202After 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 Ser83 for Cys83 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.enCardiopulmonary bypassDanger-associated molecular patternsEndocytosisImmunoparalysisInterleukin-10Peroxiredoxin 1[SDGs]SDG3journal article10.1016/j.redox.2021.102086343322102-s2.0-85111321183