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 journalArticle

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

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Bacterial Pneumonia
Neutrophils
Polyphosphates
Lung
Bradykinin
Blood Platelets
Inflammation
Neutrophil Activation
Infection
Therapeutics
Serum
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hou, Q., Liu, F., Chakraborty, A., Jia, Y., Prasad, A., Yu, H., ... Luo, H. R. (2018). Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. Science Translational Medicine, 10(435), [eaal4045]. https://doi.org/10.1126/scitranslmed.aal4045

Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. / Hou, Qingming; Liu, Fei; Chakraborty, Anutosh; Jia, Yonghui; Prasad, Amit; Yu, Hongbo; Zhao, Li; Ye, Keqiang; Snyder, Solomon H; Xu, Yuanfu; Luo, Hongbo R.

In: Science Translational Medicine, Vol. 10, No. 435, eaal4045, 04.04.2018.

Research output: Contribution to journalArticle

Hou, Q, Liu, F, Chakraborty, A, Jia, Y, Prasad, A, Yu, H, Zhao, L, Ye, K, Snyder, SH, Xu, Y & Luo, HR 2018, 'Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia', Science Translational Medicine, vol. 10, no. 435, eaal4045. https://doi.org/10.1126/scitranslmed.aal4045
Hou, Qingming ; Liu, Fei ; Chakraborty, Anutosh ; Jia, Yonghui ; Prasad, Amit ; Yu, Hongbo ; Zhao, Li ; Ye, Keqiang ; Snyder, Solomon H ; Xu, Yuanfu ; Luo, Hongbo R. / Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. In: Science Translational Medicine. 2018 ; Vol. 10, No. 435.
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