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Using an in vitro killing assay, we report here that the endogenous purine ATP augments the killing of sepsis-causing bacteria by macrophages through P2X4 receptors (P2X4Rs). Using newly developed transgenic mice expressing a bioluminescent ATP probe on the cell surface, we found that extracellular ATP levels increase during sepsis, indicating that ATP may contribute to bacterial killing in vivo. Studies with P2X4R-deficient mice subjected to sepsis confirm the role of extracellular ATP acting on P2X4Rs in killing bacteria and protecting against organ injury and death. Results with adoptive transfer of macrophages, myeloid-specific P2X4R-deficient mice, and\n                    <jats:italic>P2rx4<\/jats:italic>\n                    tdTomato reporter mice indicate that macrophages are essential for the antibacterial, antiinflammatory, and organ protective effects of P2X4Rs in sepsis. Pharmacological targeting of P2X4Rs with the allosteric activator ivermectin protects against bacterial dissemination and mortality in sepsis. We propose that P2X4Rs represent a promising target for drug development to control bacterial growth in sepsis and other infections.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.99431","type":"journal-article","created":{"date-parts":[[2018,6,6]],"date-time":"2018-06-06T11:01:10Z","timestamp":1528282870000},"source":"Crossref","is-referenced-by-count":110,"title":["Macrophage P2X4 receptors augment bacterial killing and protect against sepsis"],"prefix":"10.1172","volume":"3","author":[{"given":"Bal\u00e1zs","family":"Cs\u00f3ka","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Columbia University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n H.","family":"N\u00e9meth","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Columbia University, New York, New York, USA."},{"name":"Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, 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