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

Qingming Hou, Fei Liu, Anutosh Chakraborty, Yonghui Jia, Amit Prasad, Hongbo Yu, Li Zhao, Keqiang Ye, Solomon H. Snyder, Yuanfu Xu, Hongbo R. Luo

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish (US)
Article numbereaal4045
JournalScience translational medicine
Volume10
Issue number435
DOIs
StatePublished - Apr 4 2018

ASJC Scopus subject areas

  • Medicine(all)

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