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Author Notes:

Corresponding authors: hongbo.luo@childrens.harvard.edu (H.R.L.); xuyf@ihcams.ac.cn (Y.X.).

These authors contributed equally to this work: Q.H. and F.L.

Y.X. and H.R.L. designed the study.

Q.H., F.L., Y.J., A.P., H.Y., and L.Z. performed the experiments, collected the data, and analyzed the results.

Q.H., F.L., Y.X., and H.R.L. wrote the manuscript.

A.C., K.Y., and S.H.S. gave conceptual advice.

We thank L. Silberstein, J. Manis, and L. Chai for helpful discussions.

Cell sorting was performed at the Harvard Stem Cell Institute/Diabetes Research Center Flow Core.

The authors declare that they have no competing financial interests.


Research Funding:

Y.X. was supported by grants from the National Basic Research Program of China (2015CB964903), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016–12M-1–003 and 2017-I2M-1–015), and the Chinese National Natural Science Foundation (31471116).

H.R.L. was supported by NIH grants (R01AI103142, R01HL092020, and P01 HL095489) and a grant from the Flight Attendant Medical Research Institute (CIA 123008).

A.C. was supported by NIH grant R01DK103746.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • MAC-1

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

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Journal Title:

Science Translational Medicine


Volume 10, Number 435


, Pages eaal4045-eaal4045

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

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