XXXX Catalase Restricts Immune Function by Impairing TRPM2 Channel Activity.

@entity5568 @entity21808 @entity19 @entity26 @entity5092 @entity1360 @entity29621 @entity141
As an innate defense mechanism, macrophages produce reactive @entity26 species that weaken pathogens and serve as secondary messengers involved in immune function. The Gram-negative bacterium @entity5092 utilizes its antioxidant armature to limit the host immune response, but the mechanism behind this suppression is not defined. Here we establish that @entity5092 limits @entity141 entry in macrophages, thereby limiting actin reorganization and IL-6 production in a redox-dependent fashion. Wild type (live vaccine strain) or catalase-deficient @entity5092 (  katG) show distinct profiles in their @entity5568 scavenging rates, 1 and 0.015 pm/s, respectively. @entity19 alveolar macrophages infected with   katG display abnormally high basal intracellular @entity141 concentration that did not increase further in response to @entity5568 . Additionally,   katG-infected macrophages displayed limited @entity141 influx in response to @entity1360 , as a result of ionophore @entity5568 sensitivity. Exogenously added @entity5568 or @entity5568 generated by   katG likely oxidizes @entity1360 and alters its ability to transport @entity141 . Basal increases in cytosolic @entity141 and insensitivity to @entity5568 -mediated @entity141 entry in   katG-infected cells are reversed by the @entity141 channel inhibitors @entity29621 and @entity21808 . @entity29621 but not @entity21808 abrogated   katG-dependent increases in macrophage actin remodeling and IL-6 secretion, suggesting a role for @entity5568 -mediated @entity141 entry through the transient receptor potential melastatin 2 (TRPM2) channel in macrophages. Indeed, increases in basal @entity141 , actin polymerization, and IL-6 production are reversed in TRPM2-null macrophages infected with   katG. Together, our findings provide compelling evidence that @entity5092 catalase restricts reactive @entity26 species to temper macrophage TRPM2-mediated @entity141 signaling and limit host immune function.
