Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Yen, Wei-Chen; Wu, Yi-Hsuan; Wu, Chih-Ching; Lin, Hsin-Ru; Stern, Arnold; Chen, Shih-Hsiang; Shu, Jwu-Ching; Tsun-Yee Chiu, Daniel

G6PD is important in maintaining cellular redox homeostasis by regenerating NADPH, the substrate of NOX and NOS. The formation of superoxide by NOX is dependent on the electrons are transferred from cytoplasmic NADPH to extracellular oxygen. Superoxide can be reduced by extracellular superoxide dismutase (SOD1) to produce H 2 O 2 , which transfer into cells through aquaporin channels, or influx into cytoplasm through the chloride channel-3 to initiate intracellular signaling [44] . Since the activity of NOX is modulated by G6PD status, the pathwaymediated inflammatory response is impaired by G6PD deficiency [12] . G6PD deficiency increases the cellular susceptibility to a variety of pathogen-induced viral and bacterial infections [13, 23, 24] . Compared to the levels in normal phagocytes, G6PD-deficient phagocytes have lower levels of superoxide and other ROS needed for effective microbial killing [36, 45] . Such susceptibility to microbial infections in patients with G6PD deficiency may be due to an impaired response, the absence of NETosis [46] , and a still unknown defense mechanism. The present study shows that the inflammasome response is modulated by G6PD status and provides an additional mechanism for why G6PD deficiency increases susceptibility to infections as proposed in Fig. 8 .