Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

Balázs Csóka, Zoltán H. Németh, Ildikó Szabó, Daryl L. Davies, Zoltán V. Varga, János Pálóczi, Simonetta Falzoni, Francesco Di Virgilio, Rieko Muramatsu, Toshihide Yamashita, Pál Pacher, G. Haskó

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The macrophage is a major phagocytic cell type, and its impaired function is a primary cause of immune paralysis, organ injury, and death in sepsis. An incomplete understanding of the endogenous molecules that regulate macrophage bactericidal activity is a major barrier for developing effective therapies for sepsis. 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 P2rx4 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.

Original languageEnglish
JournalJCI insight
Volume3
Issue number11
DOIs
Publication statusPublished - Jun 7 2018

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Purinergic P2X4 Receptors
Sepsis
Macrophages
Adenosine Triphosphate
Bacteria
Ivermectin
Adoptive Transfer
Wounds and Injuries
Phagocytes
Paralysis
Transgenic Mice
Anti-Inflammatory Agents
Pharmacology

Keywords

  • Cell Biology
  • Innate immunity

Cite this

Csóka, B., Németh, Z. H., Szabó, I., Davies, D. L., Varga, Z. V., Pálóczi, J., ... Haskó, G. (2018). Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI insight, 3(11). https://doi.org/10.1172/jci.insight.99431

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. / Csóka, Balázs; Németh, Zoltán H.; Szabó, Ildikó; Davies, Daryl L.; Varga, Zoltán V.; Pálóczi, János; Falzoni, Simonetta; Di Virgilio, Francesco; Muramatsu, Rieko; Yamashita, Toshihide; Pacher, Pál; Haskó, G.

In: JCI insight, Vol. 3, No. 11, 07.06.2018.

Research output: Contribution to journalArticle

Csóka, B, Németh, ZH, Szabó, I, Davies, DL, Varga, ZV, Pálóczi, J, Falzoni, S, Di Virgilio, F, Muramatsu, R, Yamashita, T, Pacher, P & Haskó, G 2018, 'Macrophage P2X4 receptors augment bacterial killing and protect against sepsis', JCI insight, vol. 3, no. 11. https://doi.org/10.1172/jci.insight.99431
Csóka B, Németh ZH, Szabó I, Davies DL, Varga ZV, Pálóczi J et al. Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI insight. 2018 Jun 7;3(11). https://doi.org/10.1172/jci.insight.99431
Csóka, Balázs ; Németh, Zoltán H. ; Szabó, Ildikó ; Davies, Daryl L. ; Varga, Zoltán V. ; Pálóczi, János ; Falzoni, Simonetta ; Di Virgilio, Francesco ; Muramatsu, Rieko ; Yamashita, Toshihide ; Pacher, Pál ; Haskó, G. / Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. In: JCI insight. 2018 ; Vol. 3, No. 11.
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