Zhx2 accelerates sepsis by promoting macrophage glycolysis via Pfkfb3

Sepsis is a life-threatening condition with limited therapeutic options, characterized as excessive systemic inflammation and multiple organ failure. Macrophages play critical roles in sepsis pathogenesis. Metabolism orchestrates homeostasis of macrophages. However, the precise mechanism of macrophage metabolism during sepsis remains poorly elucidated. Here, we identified the key role of zinc fingers and homeoboxes (Zhx2), a ubiquitous transcription factor, in macrophage glycolysis and sepsis by enhancing Pfkfb3 expression. Mice with myeloid Zhx2 specific deletion (MKO) showed more resistant to cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced sepsis, exhibiting as prolonged survival, attenuated pulmonary injury and reduced level of pro-inflammatory cytokines. Interestingly, Zhx2 deletion conferred macrophages tolerance to LPS induced glycolysis, accompanied by reduced pro-inflammatory cytokines and lactate. Consistently, treatment of glycolytic inhibitor 2-deoxyglucose (2-DG) almost completely abrogated the protection of mice from LPS induced sepsis initiated by Zhx2 deletion in macrophages. Mechanistically, RNA-seq and chromatin immunoprecipitation (ChIP) assays confirmed that Zhx2 enhanced transcription of Pfkfb3, the glycolysis rate-limiting enzyme via binding with Pfkfb3 promoter. Furthermore, Pfkfb3 overexpression not only rescued the reduction of macrophage glycolysis caused by Zhx2 deficiency, displaying as extracellular acidification rates (ECAR) and lactate production, but also destroyed the resistance of mice to LPS induced sepsis initiated by transfer of BMDM from MKO mice. These findings highlight the novel role of transcription factor Zhx2 in sepsis via regulating Pfkfb3 expression and reprogramming macrophage metabolism, which would shed new insights into the potential strategy to intervene sepsis.