Abstract
Vibrio vulnificus is notorious for inducing rapidly progressive infections with high lethality and significant morbidity. Macrophages, being essential components of the innate immune system, play a vital role in combating infections, and their activation and effector functions are closely intertwined with metabolic reprogramming processes. However, the mechanisms governing macrophage glycolytic metabolism in response to V. vulnificus infection remain poorly elucidated. Based on our current data, we propose that NOD-like receptor 3 (NLRP3) could potentially contribute to the regulation of glycolytic metabolism in macrophages infected with V. vulnificus, though further validation is needed to confirm this relationship in both in vivo and in vitro. Upon V. vulnificus infection, NLRP3 was shown to augment glucose uptake, upregulate the aerobic glycolytic pathway, facilitate lactate release, and enhance reactive oxygen species (ROS) production. Notably, these metabolic alterations were abolished in NLRP3 knockout (KO) macrophages, as observed in both NLRP3-deficient macrophage cell lines and primary cells. We also found that the abundances of fructose 1,6-bisphosphate and 3-phosphoglyceric acid in glycolytic metabolism were decreased in V. vulnificus-infected NLRP3 KO macrophages by non-targeted metabolic flux analysis, which might be due to the reduction of PFKL that converts fructose 6-phosphate to fructose 1,6-bisphosphate in V. vulnificus-infected NLRP3 KO macrophage. These findings suggest that NLRP3 may promote inflammation in macrophages during V. vulnificus infection by driving glycolysis and increasing ROS production. The absence of these metabolic changes in NLRP3 KO macrophages underlines the crucial role of NLRP3 in modulating the immunometabolic response to V. vulnificus infection.IMPORTANCEThe results of this study demonstrate that NOD-like receptor 3 (NLRP3) is critical for metabolic reprogramming in macrophages during Vibrio vulnificus infection. NLRP3 enhances glucose uptake, upregulates glycolysis, reprograms metabolic flux, and promotes reactive oxygen species production. These findings are significant, as they reveal a previously unrecognized role of NLRP3 in regulating immune function in V. vulnificus-infected macrophages. This study identifies NLRP3 as a central mediator linking immune cell metabolism to defense against infections, providing novel insights into how innate immunity controls pathogenic bacteria and suggesting potential strategies for improving treatment or prevention of severe infections. However, further research is required to fully elucidate its impact on macrophage glycolysis in V. vulnificus-induced sepsis.