title: Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages.
abstract: Macrophages respond to changes in environmental stimuli by assuming distinct functional phenotypes, a phenomenon referred to as macrophage polarization. We generated classically (M1) and alternatively (M2) polarized macrophages--two extremes of the polarization spectrum--to compare the properties of their phagosomes. Specifically, we analyzed the regulation of the luminal pH after particle engulfment. The phagosomes of M1 macrophages had a similar buffering power and proton (equivalent) leakage permeability but significantly reduced proton-pumping activity compared with M2 phagosomes. As a result, only the latter underwent a rapid and profound acidification. By contrast, M1 phagosomes displayed alkaline pH oscillations, which were caused by proton consumption upon dismutation of superoxide, followed by activation of a voltage- and Zn(2+)-sensitive permeation pathway, likely HV1 channels. The paucity of V-ATPases in M1 phagosomes was associated with, and likely caused by, delayed fusion with late endosomes and lysosomes. The delayed kinetics of maturation was, in turn, promoted by the failure of M1 phagosomes to acidify. Thus, in M1 cells, elimination of pathogens through deployment of the microbicidal NADPH oxidase is given priority at the expense of delayed acidification. By contrast, M2 phagosomes proceed to acidify immediately in order to clear apoptotic bodies rapidly and effectively.
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Canton
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Rojyar
authors.initials: R
authors.lastname: Khezri
authors.affiliation: Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON M5C 1N8, Canada sergio.grinstein@sickkids.ca.
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
mesh_terms: D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D010588:Phagosomes / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: C510235:HVCN1 protein, human; D007473:Ion Channels; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D025262:Vacuolar Proton-Translocating ATPases