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

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

Sci Transl Med

Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center; Department of Laboratory Medicine, Children's Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA.

Published: April 2018

AI Article Synopsis

Article 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 () gene or pharmacologically inhibiting IP6K1 activity using the specific inhibitor TNP [N2-(-(trifluoromethyl)benzyl) N6-(-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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435359PMC
http://dx.doi.org/10.1126/scitranslmed.aal4045DOI Listing

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