G6PD knockdown-mediated impairment of inflammasome activation via dysregulation of p38/MAPK pathway

Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of pentose phosphate pathway to maintain cellular redox homeostasis via the production of NADPH. Through NADPH oxidase (NOX), NADPH modulates the generation of reactive oxygen species (ROS) against pathogen infection. G6PD deficient cells have low sensitivity to induce inflammation pathway for elimination of pathogen infection. Inflammasome activation is a kind of inflammatory response and plays a regulatory role in innate immunity by producing pro-inflammatory cytokines including interleukine-1β and 18 (IL-1β and IL-18). However, the role of G6PD in the activation of inflammasome remains elusive. To investigate whether G6PD modulates inflammasome activation, peripheral blood mononuclear cells (PBMCs) were isolated from well-known G6PD genetic variants in Taiwan and differentiated into macrophage-liked cells by phorbol 12-myristate 13-acetate (PMA) treatment. The signal 1 and 2 pathways of inflammasome were activated by lipopolysaccharides (LPS) and adenosine triphosphate (ATP) stimulation, respectively. During inflammasome activation, a decreased secretion of IL-1β was observed in PMA-primed G6PD deficient PBMCs as compared with their counterparts. We further used human monocytic cells (THP-1) as model to delineate whether the expression of molecules in inflammasome signal 1 and 2 pathway could be modulated by G6PD. Indeed, inflammasome activation-induced IL-1β secretion and p38 phosphorylation of signal 1 pathway were downregulated upon G6PD knockdown in THP-1 cells. In contrast, the effect of G6PD on signal 2 pathway was not significant in THP-1 cells. Taken together, these results suggest that G6PD deficiency down regulates inflammasome activation via MAPK pathway and the detail mechanism is currently under investigation.