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 level of ROS can have significant consequence on various cellular function [8, [12] [13] [14] 36, 38, [47] [48] [49] . Cytotoxic level of ROS, such as oxidative burst in phagocytic cells, participates in host defense by direct killing of foreign pathogen [48] . On the other hand, cytoregulatory level of ROS mediates intracellular signaling that maintain proper redox environment and regulate many cellular signaling pathways [14, 49, 50] . In the present study, we provide evidence to support the notion that cytoregulatory level of ROS influenced p38/MAPK/AP-1 pathway and bactericidal effect in G6PD deficient cells. The pathway of inflammasome activation involves two signals, including priming (signal 1) and activation (signal 2) [25] . Our results indicate that G6PD deficiency can influence p38/MAPK/AP-1 pathway (signal 1), but not the expression of inflammasome subunit influenced by signal 2 suggesting that low concentration of ROS in G6PD deficiency can affect signal 1 but not signal 2. Furthermore, the expression of phospho-p38 and pro-IL-1β has been found to be improved in low-dose (0.1 mM) H 2 O 2 treated cells (Fig. 6G-J) . In contrast, IL-1β secretion has been detected under high level of H 2 O 2 stimulation (Fig. S3 ). High concentration of ROS leads cells undergo apoptosis or pyroptosis, which is the common programmed cell death upon inflammasome activation. In contrast, cyto-regulatory level of ROS is important for cells to regulate cellular signaling transduction [50] . All in all, ROS can affect inflammasome activation via both signals 1 and 2 at high concentration (cytotoxic level), whereas low concentration of ROS is involved in regulating only signal 1 of inflammasome activation.