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

The activation of the NLRP3 inflammasome is ROS dependent [33, 34] and is mediated by the NOX pathway [35] . Decreased ROS production is observed in G6PD-deficient granulocytes upon lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) stimulation and such abnormality has been attributed to impaired NOX signaling [14, 36, 37] . Increased susceptibility to pathogen infections in G6PDdeficient cells is due to an insufficient ROS-triggered inflammatory response [13] . These findings provide support for the notion that G6PD deficiency impairs ROS production via the NOX signaling pathway. The effect of G6PD on NLRP3 inflammasome activation deserves further attention. In the current study, a decrease in IL-1β was observed in the PBMCs of patients with G6PD deficiency and in G6PD-kd THP-1 cells. This led to an investigation of the role of G6PD in inflammasome activation and its association with the bactericidal effect in phagocytes. Mechanistically, G6PD deficiency provides less NADPH as a substrate for NOX, causing less ROS generation to activate the inflammasome.