Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonasaeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M(-/-) animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M(-/-) animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

译文

:败血症导致相对免疫抑制状态,使重症患者容易受到继发感染并增加死亡率。从败血病患者和实验动物中分离出的单核细胞表现出“失活”表型,其特征是炎症和抗菌反应减弱,包括对LPS的反应不足。我们调查了LPS / TLR4轴及其抑制剂IL-1受体相关激酶-M(IRAK-M)在调节败血症的免疫抑制中的作用,该模型使用的是腹膜炎诱导的败血症的鼠模型,随后是气管内继发性攻击铜绿假单胞菌。与非败血性对照相比,经气管内假单胞菌攻击时,败血性小鼠肺泡巨噬细胞功能受损,死亡率增加。败血症后肺中TLR2和TLR4表达未改变,而IRAK-M水平上调。与野生型WT小鼠相比,IRAK-M缺陷型败血症小鼠的巨噬细胞离体产生更高水平的促炎细胞因子,体内产生更高的共刺激分子表达。败血症和继发性肺内细菌攻击后,与WT小鼠相比,IRAK-M(-/-)动物具有更高的存活率并改善了从肺和血液中的细菌清除率。此外,IRAK-M(-/-)动物中观察到增加的肺趋化因子和炎性细胞因子的产生,导致嗜中性粒细胞向空域的募集增加。总的来说,这些发现表明IRAK-M介导了先天免疫的关键方面,这些固有方面在败血症期间导致免疫功能低下。

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