Role of phagosomal redox-sensitive trp channel TRPM2 in regulating bactericidal activity of macrophages

Abstract

Acidification of macrophage (MΦ) phagosomes serves an important bactericidal function. We show here that the redox-sensitive trp cation channel TRPM2 expressed in the phagosomal membrane regulates MΦ bactericidal activity through the activation of phagosomal acidification. Measurement of TRPM2 current in phagosomes identified TRPM2 as a functional redox-sensitive cation channel localized in phagosomal membrane. Simultaneous measurements of phagosomal Ca2+ changes and phagosome acidification in MΦs undergoing phagocytosis demonstrated the requisite role of TRPM2 in mediating efflux of cations and phagosomal acidification during the process of phagosome maturation. Acidification in phagosomes was significantly reduced in MΦs isolated from Trpm2−/− mice as compared to wild type and acidification was coupled to reduced bacterial clearance in Trpm2−/− mice. Trpm2+/+ MΦs treated with the proton inhibitor bafilomycin showed reduced bacterial clearance similar to Trpm2−/− MΦs. 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 MΦs.