Sugitani Norie, Henkel Matthew, Partyka Jessica, Applegate Alexander, Kemp Felicia, Byersdorfer Craig A, Eddens Taylor, Campfield Brian T
Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Department of Pediatrics, Division of Blood and Marrow Transplantation and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Immunol. 2025 Mar 6;16:1558252. doi: 10.3389/fimmu.2025.1558252. eCollection 2025.
Bacterial pneumonia is a burdensome, costly disease and increasingly challenging to treat due to antibiotic resistance. Complex host-pathogen interactions regulate protective immunity. Neutrophils play a central role in pulmonary bacterial immunity, and mechanistic understanding of neutrophil functions in bacterial pneumonia has potential clinical and fundamental application. Nuclear receptor 4a1 (Nr4a1), a member of the nuclear orphan receptor family, has been described to regulate inflammation and immune development in a cell type-specific manner, but its role in pulmonary host defense is not well understood.
Wild-type (WT) and mice, as well as bone marrow chimeric and Gr-1+ antibody depleted mice, were infected with Klebsiella pneumoniae and assessed for bacterial burden in the lung and spleen, gene transcription, protein levels, histology and cellular abundance by flow cytometry in the lung. WT and neutrophils were exposed to live to quantify bacterial killing, as well as bulk RNA sequencing to assess transcriptomic differences.
Nr4a1-deficient mice are highly susceptible to Klebsiella pneumoniae pneumonia, which was mediated by expression in immune cells. Gr-1+ antibody depletion ameliorated the Nr4a1-dependent phenotype. , Nr4a1-deficient neutrophils had impaired bactericidal capacity, and transcriptomic analysis identified an Nr4a1-dependent host defense program in neutrophils.
Neutrophil expression is critical for defense against infection by regulating the neutrophil transcriptome. These findings suggest targeting signaling pathways in neutrophils may be useful for bacterial pneumonia treatment.
细菌性肺炎是一种负担沉重、代价高昂的疾病，由于抗生素耐药性，其治疗难度日益增大。复杂的宿主-病原体相互作用调节着保护性免疫。中性粒细胞在肺部细菌免疫中起核心作用，对细菌性肺炎中中性粒细胞功能的机制性理解具有潜在的临床和基础应用价值。核受体4a1（Nr4a1）是核孤儿受体家族的成员，已被描述以细胞类型特异性方式调节炎症和免疫发育，但其在肺部宿主防御中的作用尚不清楚。
用肺炎克雷伯菌感染野生型（WT）和Nr4a1-/-小鼠，以及骨髓嵌合和Gr-1+抗体清除的小鼠，并通过流式细胞术评估肺和脾中的细菌负荷、基因转录、蛋白质水平、组织学和细胞丰度。将WT和Nr4a1-/-中性粒细胞暴露于活的肺炎克雷伯菌中以量化细菌杀伤，并进行批量RNA测序以评估转录组差异。
Nr4a1缺陷小鼠对肺炎克雷伯菌肺炎高度易感，这是由免疫细胞中的Nr4a1表达介导的。Gr-1+抗体清除改善了Nr4a1依赖性表型。此外，Nr4a1缺陷的中性粒细胞杀菌能力受损，转录组分析确定了中性粒细胞中依赖Nr4a1的宿主防御程序。
中性粒细胞Nr4a1表达通过调节中性粒细胞转录组对抵御肺炎克雷伯菌感染至关重要。这些发现表明，靶向中性粒细胞中的Nr4a1信号通路可能对细菌性肺炎治疗有用。
