title: Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages.
abstract: Acidification of macrophage phagosomes serves an important bactericidal function. We show here that the redox-sensitive transient receptor potential (TRP) cation channel TRPM2 is expressed in the phagosomal membrane and regulates macrophage bactericidal activity through the activation of phagosomal acidification. Measurement of the TRPM2 current in phagosomes identified TRPM2 as a functional redox-sensitive cation channel localized in the phagosomal membrane. Simultaneous measurements of phagosomal Ca2+changes and phagosome acidification in macrophages undergoing phagocytosis demonstrated that TRPM2 was required to mediate the efflux of cations and for phagosomal acidification during the process of phagosome maturation. Acidification in phagosomes was significantly reduced in macrophages isolated fromTrpm2-/-mice as compared to wild type, and acidification was coupled to reduced bacterial clearance inTrpm2-/-mice.Trpm2+/+macrophages treated with the vacuolar H+-ATPase inhibitor bafilomycin showed reduced bacterial clearance, similar to that inTrpm2-/-macrophages. Direct activation of TRPM2 using adenosine diphosphate ribose (ADPR) induced both phagosomal acidification and bacterial killing. These data collectively demonstrate that TRPM2 regulates phagosomal acidification, and is essential for the bacterial killing function of macrophages.
authors.affiliation: Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Anke
authors.identifier: 0000-0001-5055-1407
authors.initials: A
authors.lastname: Di
authors.affiliation: Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Tomohiro
authors.identifier: 0000-0003-0027-7758
authors.initials: T
authors.lastname: Kiya
authors.affiliation: Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA abmalik@uic.edu.
authors.forename: Asrar B
authors.identifier: 0000-0002-8205-7128
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015640:Ion Channel Gating; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D008297:Male; D018345:Mice, Knockout; D050296:Microbial Viability; D010084:Oxidation-Reduction; D010588:Phagosomes / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000502:physiology; D018805:Sepsis / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000502:physiology; D050053:TRPM Cation Channels / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000143:Acids; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse
keywords: Bactericidal activity; Ion channel; Phagosome