Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia

• DOI: 10.1126/scitranslmed.aal4045
• Publication Date: 2018-04-04T18:05:41Z
• Authors: Qingming Hou; Fei Liu; Anutosh Chakraborty; Yonghui Jia; Amit Prasad; Hongbo Yu; Li Zhao; Keqiang Ye; Solomon H. Snyder; Yuanfu Xu; Hongbo R. Luo
• Keywords: Bacterial pneumonia

The significance of developing host-modulating personalized therapies to counteract the growing threat antimicrobial resistance is well-recognized because such cannot be overcome using microbe-centered strategies alone. Immune host defenses must finely controlled during infection balance pathogen clearance with unwanted inflammation-induced tissue damage. Thus, an ideal treatment would enhance bactericidal activity while preventing neutrophilic inflammation, which can induce We report that disrupting inositol hexakisphosphate kinase 1 (Ip6k1) gene or pharmacologically inhibiting IP6K1 specific inhibitor TNP [N2-(m-(trifluoromethyl)benzyl) N6-(p-nitrobenzyl)purine] efficiently and effectively enhanced bacterial killing but reduced pulmonary neutrophil accumulation, minimizing lung damage caused by both Gram-positive Gram-negative pneumonia. IP6K1-mediated inorganic polyphosphate (polyP) production platelets was essential for infection-induced neutrophil-platelet aggregate (NPA) formation facilitated accumulation in alveolar spaces inhibition serum polyP levels, regulated NPAs triggering bradykinin pathway bradykinin-mediated activation. we identified a mechanism enhances simultaneously suppressing neutrophil-mediated is, therefore, legitimate therapeutic target disease.