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

A number of redox-related transcription factors are modulated by G6PD status, indicating the importance of G6PD in cellular redox homeostasis. Hemolytic crisis, diabetes [59] , hypertension [6] , infectious diseases [46, 60] and protection against malaria are associated with G6PD deficiency. That patients with G6PD deficiency are susceptible to infection may involve a novel mechanism that includes impaired inflammasome activation. Moreover, NADPH is also the substrate for many protective enzymes. Antioxidant defences may play a role in G6PD-redulated iflammasome activation. NAD(P)H:quinone oxidoreductase-1 (NQO-1) is a major quinone reductases, which requires NADPH as electron donor to catalyze quinones to hydroquinone. The enzyme also plays an antioxidant enzyme in cellular redox homeostasis [61] . The induction of NQO-1 can be mediated by Nrf2-mediated mechanism under a variety of stress responses presumably as a cellular protective system [62, 63] . In terms of inflammatory response, NQO-1 as an inhibitor in immune response by promoting IκB-ζ degradation leading to impaired TLR-mediated the production of cytokines [64] . Glutathione is also as antioxidant and plays critical role in many metabolic processes. Our previous metabolomics studies have shown that alteration of G6PD status affects cellular metabolic pathway [9, 65] . Abnormal glycerophospholipid metabolism in G6PD deficient embryos leads to defective embryonic development [65] . G6PD deficient cells are unable to regenerate enough NADPH under a stressful situation then rapid switch to GSH biosynthetic supply, which causes energy crisis and ineffective AMPK activation [9] . However, whether G6PD deficiency affected the inflammasome activation via the change of antioxidants or metabolites needs to be further investigated. Since infectious and metabolic diseases in patients with G6PD deficiency may be more severe than in patients with a normal level of G6PD, we concur with the notion that an escalating diagnostic algorithm should include a determination of G6PD activity in these patients [46] .