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

• Type of Material: Article
• Authors: Qingming Hou, Harvard Medical School; Fei Liu, Chinese Academy of Medical Sciences; Anutosh Chakraborty, Johns Hopkins University; Yonghui Jia, Harvard Medical School; Amit Prasad, Harvard Medical School; Hongbo Yu, Veteran Affairs Boston Healthcare System; Li Zhao, Harvard Medical School; Keqiang Ye, Emory University; Solomon H. Snyder, Johns Hopkins University; Yuanfu Xu, Chinese Academy of Medical Sciences; Hongbo R. Luo, Harvard Medical School
• Language: English
• Date: 2018-04-04
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aal4045
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 10
• Issue: 435
• Start Page: eaal4045
• End Page: eaal4045
• Grant/Funding Information: A.C. was supported by NIH grant R01DK103746.; 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).
• Keywords: ACCUMULATION; Life Sciences & Biomedicine; AUGMENTS; HEMOSTASIS; POLYPHOSPHATE; MAC-1; Science & Technology; Cell Biology; Research & Experimental Medicine; ACUTE LUNG INJURY; PHOSPHATASE; P-SELECTIN; Medicine, Research & Experimental; RECRUITMENT; PLATELET
• Research Categories: Health Sciences, Pathology; Health Sciences, Pharmacology; Biology, Cell

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.