Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.

中文翻译：

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肺泡巨噬细胞在炎症后发生表观遗传改变，导致长期肺免疫麻痹。

脓毒症和创伤会导致炎症和医院获得性肺炎的易感性升高。由于巨噬细胞的吞噬作用在控制细菌中起关键作用，我们研究了炎症消退后巨噬细胞的吞噬活性。在原发性肺炎消退后，鼠肺泡巨噬细胞 (AMs) 在数周内表现出较差的吞噬能力。这些瘫痪的 AMs 是从接受过耐受性训练的表观遗传计划的常驻 AMs 发展而来的。这种适应不是由直接遇到病原体引起的，而是由原发感染解决后局部建立的继发性免疫抑制信号引起的。信号调节蛋白 α (SIRPα) 在建立诱导耐受性训练的微环境中发挥了关键作用。在患有全身性炎症的人类中，在炎症消退六个月后，AMs 和循环单核细胞仍显示出与重编程一致的变化。SIRPα 的抗体阻断在体外恢复了危重患者单核细胞的吞噬作用，这表明了一种预防医院获得性肺炎的潜在策略。