STAT1 Employs Myeloid Cell-Extrinsic Mechanisms to Regulate the Neutrophil Response and Provide Protection against Invasive Klebsiella pneumoniae Lung Infection.
STAT1 Employs Myeloid Cell-Extrinsic Mechanisms to Regulate the Neutrophil Response and Provide Protection against Invasive Klebsiella pneumoniae Lung Infection.
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DOI：
10.4049/immunohorizons.2300104
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发表时间：
2024-01-01
期刊：
影响因子：
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通讯作者：
Lee JS
中科院分区：
文献类型：
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作者：
Gonzalez-Ferrer S;Peñaloza HF;van der Geest R;Xiong Z;Gheware A;Tabary M;Kochin M;Dalton K;Zou H;Lou D;Lockwood K;Zhang Y;Bain WG;Mallampalli RK;Ray A;Ray P;Van Tyne D;Chen K;Lee JS
肺炎克雷伯菌 (KP) 是一种细胞外革兰氏阴性细菌，可引起下呼吸道、尿路和血液感染。 STAT1 是一种主转录因子，可在稳态条件下维持 T 细胞静止。尽管 STAT1 有助于防御急性 KP 肺内感染的全身扩散，但 STAT1 对 T 细胞稳态的调节是否会影响急性细菌感染和损伤期间肺宿主的防御尚不清楚。使用临床 KP 呼吸道分离株和肺炎小鼠模型，我们发现 STAT1 缺陷导致早期中性粒细胞占主导地位的转录谱，并且中性粒细胞在肺部招募，然后发生广泛的细菌传播和肺损伤发展。然而，骨髓细胞 STAT1 对于控制 KP 增殖和传播来说是可有可无的，因为骨髓细胞特异性 STAT1 缺陷 (LysMCre/WT;Stat1fl/fl) 小鼠的肺、肝脏和肾脏中的细菌负荷与野生型同窝小鼠相似。令人惊讶的是，在 KP 感染期间，产生 IL-17 的 CD4+ T 细胞在早期就渗入了 Stat1−/− 小鼠的肺部。肺部 Th17 细胞的增加并不是由于预先存在的针对 KP 的免疫力，并且与循环而不是组织驻留的 CD4+ T 细胞一致。然而，用抗 IL-17RC 阻断全局 IL-17 信号传导会导致 KP 的增殖和传播增加，这表明其他先天免疫细胞提供的 IL-17 对于防御 KP 至关重要。相比之下，CD4+ T 细胞的耗竭减少了 Stat1−/− 鼠肺细菌负荷，表明在整体 STAT1 缺陷的情况下早期 CD4+ T 细胞激活是致病的。总而言之，我们的研究结果表明，STAT1 利用骨髓细胞外在机制来调节中性粒细胞反应，并通过限制肺部非特异性 CD4+ T 细胞激活和免疫病理学来提供针对侵袭性 KP 的保护。
Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread bacterial dissemination and lung injury development. Yet, myeloid cell STAT1 was dispensable for control of KP proliferation and dissemination, because myeloid cell–specific STAT1-deficient (LysMCre/WT;Stat1fl/fl) mice showed bacterial burden in the lung, liver, and kidney similar to that of their wild-type littermates. Surprisingly, IL-17–producing CD4+ T cells infiltrated Stat1−/− murine lungs early during KP infection. The increase in Th17 cells in the lung was not due to preexisting immunity against KP and was consistent with circulating rather than tissue-resident CD4+ T cells. However, blocking global IL-17 signaling with anti–IL-17RC administration led to increased proliferation and dissemination of KP, suggesting that IL-17 provided by other innate immune cells is essential in defense against KP. Contrastingly, depletion of CD4+ T cells reduced Stat1−/− murine lung bacterial burden, indicating that early CD4+ T cell activation in the setting of global STAT1 deficiency is pathogenic. Altogether, our findings suggest that STAT1 employs myeloid cell–extrinsic mechanisms to regulate neutrophil responses and provides protection against invasive KP by restricting nonspecific CD4+ T cell activation and immunopathology in the lung.