Chronic granulomatous disease (CGD) is caused by mutations in genes that encode the
NADPH-oxidase and result in a failure of phagocytic cells to produce
reactive oxygen species (ROS) via this
enzyme system. Patients with CGD are highly susceptible to
infections and often suffer from inflammatory disorders; the latter occurs in the absence of
infection and correlates with the spontaneous production of inflammatory
cytokines. This clinical feature suggests that
NADPH-oxidase-derived ROS are not required for, or may even suppress, inflammatory processes. Experimental evidence, however, implies that ROS are in fact required for inflammatory
cytokine production. By using a myeloid cell line devoid of a functional
NADPH-oxidase and primary CGD cells, we analyzed intracellular
oxidants, signs of oxidative stress, and inflammatory
cytokine production. Herein, we demonstrate that phagocytes lacking a functional
NADPH-oxidase, namely primary CGD phagocytes and a gp91phox-deficient cell line, display elevated levels of ROS derived from mitochondria. Accordingly, these cells, despite lacking the major source of cellular ROS, display clear signs of oxidative stress, including an induced expression of
antioxidants and altered oxidation of cell surface
thiols. These observed changes in redox state were not due to abnormalities in mitochondrial mass or membrane integrity. Finally, we demonstrate that increased mitochondrial ROS enhanced phosphorylation of ERK1/2, and induced production of
IL8, findings that correlate with previous observations of increased MAPK activation and inflammatory
cytokine production in CGD cells. Our data show that elevated baseline levels of mitochondria-derived
oxidants lead to the counter-intuitive observation that CGD phagocytes are under oxidative stress and have enhanced MAPK signaling, which may contribute to the elevated basal production of inflammatory
cytokines and the sterile inflammatory manifestations in CGD.