title: The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis.
abstract: A favorable outcome following acute bacterial infection depends on the ability of phagocytic cells to be recruited and properly activated within injured tissues. Calcium (Ca(2+)) is a ubiquitous second messenger implicated in the functions of many cells, but the mechanisms involved in the regulation of Ca(2+) mobilization in hematopoietic cells are largely unknown. The monovalent cation channel transient receptor potential melastatin (TRPM) 4 is involved in the control of Ca(2+) signaling in some hematopoietic cell types, but the role of this channel in phagocytes and its relevance in the control of inflammation remain unexplored. In this study, we report that the ablation of the Trpm4 gene dramatically increased mouse mortality in a model of sepsis induced by cecal ligation and puncture. The lack of the TRPM4 channel affected macrophage population within bacteria-infected peritoneal cavities and increased the systemic level of Ly6C(+) monocytes and proinflammatory cytokine production. Impaired Ca(2+) mobilization in Trpm4(-/-) macrophages downregulated the AKT signaling pathway and the subsequent phagocytic activity, resulting in bacterial overgrowth and translocation to the bloodstream. In contrast, no alteration in the distribution, function, or Ca(2+) mobilization of Trpm4(-/-) neutrophils was observed, indicating that the mechanism controlling Ca(2+) signaling differs among phagocytes. Our results thus show that the tight control of Ca(2+) influx by the TRPM4 channel is critical for the proper functioning of monocytes/macrophages and the efficiency of the subsequent response to infection.
authors.affiliation: INSERM U699, Paris F-75018, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Serafini
authors.forename: Albert
authors.initials: A
authors.lastname: Dahdah
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Barbet
authors.forename: Marie
authors.initials: M
authors.lastname: Demion
authors.forename: Tarik
authors.initials: T
authors.lastname: Attout
authors.forename: Grégory
authors.initials: G
authors.lastname: Gautier
authors.forename: Michelle
authors.initials: M
authors.lastname: Arcos-Fajardo
authors.forename: Hervé
authors.initials: H
authors.lastname: Souchet
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Jouvin
authors.forename: François
authors.initials: F
authors.lastname: Vrtovsnik
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kinet
authors.forename: Marc
authors.initials: M
authors.lastname: Benhamou
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
authors.forename: Pierre
authors.initials: P
authors.lastname: Launay
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050053:TRPM Cation Channels / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
chemical_list: D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse