BackgroundStreptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk), a key signaling protein controlling the activation of various immune cells, including macrophages and neutrophils. The aim of this study was to determine whether ibrutinib treatment ameliorates acute lung inflammation during pneumococcal pneumonia.MethodsMice were treated orally with ibrutinib and the effect on acute pulmonary inflammation elicited by the gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during ceftriaxone-treated pneumococcal pneumonia was assessed.ResultsTreatment with ibrutinib prior to and after intranasal LTA instillation reduced alveolar macrophage activation, neutrophil influx, cytokine release and plasma leakage into the lung. Postponed treatment with ibrutinib supplementing antibiotic therapy during ongoing pneumococcal pneumonia did not impair bacterial killing in lung, blood and spleen. In this setting, ibrutinib reduced alveolar macrophage and systemic neutrophil activation and substantially diminished further monocyte and neutrophil influx in the lung. In vitro, ibrutinib inhibited macrophage TNF secretion and neutrophil activation upon LTA and pneumococcal stimulation.ConclusionsTaken together, these data indicate that the Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses during acute pulmonary inflammation evoked by LTA and antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting.

中文翻译：

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Btk 抑制剂依鲁替尼可降低鼠肺炎球菌肺炎期间肺中的炎性骨髓细胞反应

背景肺炎链球菌是社区获得性肺炎和败血症的主要病原体。肺炎球菌肺炎期间压倒性的肺部炎症可能会妨碍肺功能。Ibrutinib 是 Bruton 酪氨酸激酶 (Btk) 的不可逆抑制剂，Btk 是控制各种免疫细胞（包括巨噬细胞和中性粒细胞）活化的关键信号蛋白。本研究的目的是确定依鲁替尼治疗是否能改善肺炎球菌肺炎期间的急性肺部炎症。方法小鼠口服依鲁替尼，以及对革兰氏阳性细菌细胞壁成分脂磷壁酸 (LTA) 和头孢曲松期间引起的急性肺部炎症的影响评估了治疗的肺炎球菌肺炎。结果在鼻内 LTA 滴注之前和之后用依鲁替尼治疗减少了肺泡巨噬细胞活化、中性粒细胞流入、细胞因子释放和血浆渗漏到肺中。在肺炎球菌肺炎期间推迟使用依鲁替尼补充抗生素治疗不会损害肺、血液和脾脏中的细菌杀灭。在这种情况下，依鲁替尼减少了肺泡巨噬细胞和全身中性粒细胞的活化，并显着减少了肺中单核细胞和中性粒细胞的进一步流入。在体外，依鲁替尼在 LTA 和肺炎球菌刺激下抑制巨噬细胞 TNF 分泌和中性粒细胞活化。