Table_1_Contribution of Puma to Inflammatory Resolution During Early Pneumococcal Pneumonia.xlsx

Apoptosis of cells at the site of infection is a requirement for shutdown of inflammatory signaling, avoiding tissue damage, and preventing progression of sepsis. Puma+/+ and Puma-/- mice were challenged with TIGR4 strain pneumococcus and cytokines were quantitated from lungs and blood using a magnetic bead panel analysis. Puma-/- mice exhibited higher lung and blood cytokine levels of several major inflammatory cytokines, including IL-6, G-CSF, RANTES, IL-12, IFN-ϒ, and IP-10. Puma-/- mice were more susceptible to bacterial dissemination and exhibited more weight loss than their wild-type counterparts. RNA sequencing analysis of whole pulmonary tissue revealed Puma-dependent regulation of Nrxn2, Adam19, and Eln. Enrichment of gene ontology groups differentially expressed in Puma-/- tissues were strongly correlated to IFN-β and -ϒ signaling. Here, we demonstrate for the first time the role of Puma in prohibition of the cytokine storm during bacterial pneumonia. These findings further suggest a role for targeting immunomodulation of IFN signaling during pulmonary inflammation. Additionally, our findings suggest previously undemonstrated roles for genes encoding regulatory and binding proteins during the early phase of the innate immune response of pneumococcal pneumonia.

感染部位的细胞凋亡是终止炎症信号通路、规避组织损伤并阻止败血症进展的必要前提。研究人员采用TIGR4菌株肺炎链球菌感染Puma野生型（Puma+/+）与Puma基因敲除型（Puma-/-）小鼠，并通过磁珠面板分析（magnetic bead panel analysis）对肺组织与血液中的细胞因子进行定量检测。结果显示，Puma-/-小鼠的肺部及血液中多种核心炎症细胞因子（包括IL-6、G-CSF、RANTES、IL-12、IFN-γ、IP-10）的表达水平显著高于野生型同窝小鼠。Puma基因敲除小鼠更易发生细菌播散，且体重下降幅度显著大于野生型对照组。对全肺组织开展RNA测序（RNA sequencing）分析发现，Nrxn2、Adam19及Eln的表达受Puma依赖性调控。Puma-/-小鼠组织中差异表达基因的基因本体（Gene Ontology，GO）功能富集组与IFN-β及IFN-γ信号通路具有极强的相关性。本研究首次证实了Puma在细菌性肺炎进程中抑制细胞因子风暴的作用。上述研究结果进一步提示，在肺部炎症期间靶向调控IFN信号通路的免疫调节策略具备潜在研究与应用价值。此外，本研究还揭示了此前未被报道的、编码调控蛋白与结合蛋白的基因在肺炎链球菌肺炎先天免疫应答早期阶段的关键作用。