Cu,Zn-superoxide dismutase (SOD) is known to be a locus of mutation in familial amyotrophic lateral sclerosis (FALS). Transgenic mice that express a mutant Cu,Zn-SOD, Because the levels of total Cu,Zn-SOD activity in these transgenic mice are greater than normal, the plausible interpretation of the ALS symptoms in these mice is that the mutant is in some way cytotoxic. The nature of this cytotoxic gain-offunction of the FALS mutants is yet to be identified.In addition to the usual superoxide dismutation activity, Cu,Zn-SOD has a peroxidative function that utilizes its own dismutation product, H202, as a substrate (17)(18)(19). During this reaction, the enzyme becomes inactivated in a relatively short period of time. However, this inactivation can be prevented by various anionic radical scavengers (18)(19)(20). Previous investigations from our laboratory (18,19) have shown that, during these reactions, free radicals, such as the hydroxyl radical ('OH), and scavenger-derived radicals are generated and some of these free radicals can escape from the active channel to the bulk solution. Because the enzymic activity is protected by small anions against H202 inactivation and concomitant generation of the anion-derived radicals, Cu,Zn-SOD behaves as an enzyme that catalyzes the formation of free radicals using anionic scavengers and H202 as substrates (18,19). These anionic scavengers, which become free radicals in this peroxidative reaction, include some neurotransmitters such as glutamate and taurine (19).We investigated whether there are any differences in the free radical-generating function between the wild-type and FALS mutant Cu,Zn-SOD. For this purpose, we cloned the wild-type and G93A cDNA of human Cu,Zn-SOD, overexpressed them in insect cells (Sf9), purified proteins, and measured their enzymic activities. Our results revealod-thatthe G93A and the wild-type Cu,Zn-SOD have identical dismutation activities. However, the free radical-generating function of the G93A mutant measured by the spin trapping method is enhanced relative to that of the wild-type enzyme. We found that this enhancement is due to a small decrease in the value of Km for H202. This gain-of-function, in part, may provide an explanation for the association of the FALS Cu,Zn-SOD mutants to ALS (21).
Summary The cellular mechanisms controlling infection-induced emergency granulopoiesis are poorly defined. Here we found that reactive oxygen species (ROS) concentrations in the bone marrow (BM) were elevated during acute infection in a phagocytic NADPH oxidase-dependent manner in myeloid cells. Gr1+ myeloid cells were uniformly distributed in the BM, and all c-Kit+ progenitor cells were adjacent to Gr1+ myeloid cells. Inflammation-induced ROS production in the BM played a critical role in myeloid progenitor expansion during emergency granulopoiesis. ROS elicited oxidation and deactivation of phosphatase and tensin homolog (PTEN), resulting in up-regulation of PtdIns(3,4,5)P3 signaling in BM myeloid progenitors. We further revealed that BM myeloid cell-produced ROS stimulated proliferation of myeloid progenitors via a paracrine mechanism. Taken together, our results establish that phagocytic NADPH oxidase-mediated ROS production by BM myeloid cells plays a critical role in mediating emergency granulopoiesis during acute infection.
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