Bacterial pneumonia is a significant cause of morbidity, mortality, and health care expenditures. Optimum neutrophil recruitment and their function are critical defense mechanisms against respiratory pathogens. The nucleotide-binding oligomerization domain-like receptor (NLRP) 6 controls gut microbiota and immune response to systemic and enteric infections. However, the importance of NLRP6 in neutrophil homeostasis following lung infection remains elusive. To investigate the role of NLRs in neutrophil homeostasis, we used Nlrp6 gene-deficient (Nlrp6^−/−) mice in a model of Klebsiella pneumoniae-induced pneumonia-derived sepsis. We demonstrated that NLRP6 is critical for host survival, bacterial clearance, neutrophil influx, and CXC-chemokine production. Kp-infected Nlrp6^−/− mice have reduced numbers of hematopoietic stem cells and granulocyte-monocyte progenitors but increased retention of matured neutrophils in bone marrow. Neutrophil extracellular trap (NET) formation and NET-mediated bacterial killing were also impaired in Nlrp6^−/− neutrophils in vitro. Furthermore, recombinant CXCL1 rescued the impaired host defense, granulopoietic response, and NETosis in Kp-infected Nlrp6^−/− mice. Using A/J background mice and co-housing experiments, our findings revealed that the susceptible phenotype of Nlrp6^−/− mice is not strain-specific and gut microbiota-dependent. Taken together, these data unveil NLRP6 as a central regulator of neutrophil recruitment, generation, and function during bacterial pneumonia followed by sepsis.

细菌性肺炎是发病率、死亡率和医疗保健支出的重要原因。中性粒细胞的最佳募集及其功能是抵抗呼吸道病原体的关键防御机制。核苷酸结合寡聚化结构域样受体 (NLRP) 6 控制肠道微生物群和对全身和肠道感染的免疫反应。然而，NLRP6 在肺部感染后中性粒细胞稳态中的重要性仍不清楚。为了研究 NLR 在中性粒细胞稳态中的作用，我们在肺炎克雷伯菌模型中使用了 Nlrp6基因缺陷 ( Nlrp6 ^-/- ) 小鼠-诱导的肺炎衍生败血症。我们证明 NLRP6 对于宿主存活、细菌清除、中性粒细胞流入和 CXC 趋化因子产生至关重要。Kp 感染的Nlrp6 ^-/-小鼠造血干细胞和粒细胞-单核细胞祖细胞数量减少，但成熟中性粒细胞在骨髓中的保留增加。中性粒细胞胞外陷阱 (NET) 的形成和 NET 介导的细菌杀灭也在Nlrp6 ^-/-中性粒细胞中受损。此外，重组 CXCL1 挽救了 Kp 感染的Nlrp6 ^-/-小鼠中受损的宿主防御、粒细胞生成反应和 NETosis 。使用 A/J 背景小鼠和共同饲养实验，我们的研究结果表明，易感表型Nlrp6 ^-/-小鼠不是品系特异性和肠道微生物群依赖性的。总而言之，这些数据揭示了 NLRP6 在细菌性肺炎和脓毒症期间作为中性粒细胞募集、生成和功能的中央调节因子。