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Macrophages play critical roles in sepsis pathogenesis. Metabolism orchestrates homeostasis of macrophages. However, the precise mechanism of macrophage metabolism during sepsis remains poorly elucidated. In this study, we identified the key role of zinc fingers and homeoboxes (Zhx2), a ubiquitous transcription factor, in macrophage glycolysis and sepsis by enhancing 6-phosphofructo-2-kinase\/fructose-2,6-biphosphatase 3 (Pfkfb3) expression. Mice with myeloid Zhx2-specific deletion (abbreviated as MKO) showed more resistance to cecal ligation and puncture and LPS-induced sepsis, exhibiting as prolonged survival, attenuated pulmonary injury, and reduced level of proinflammatory cytokines, such as TNF-\u03b1, IL-6, and IL-1\u03b2. Interestingly, Zhx2 deletion conferred macrophage tolerance to LPS-induced glycolysis, accompanied by reduced proinflammatory cytokines and lactate. Consistently, treatment of glycolytic inhibitor 2-deoxyglucose almost completely abrogated the protection of mice from LPS-induced sepsis initiated by Zhx2 deletion in macrophages. RNA sequencing and chromatin immunoprecipitation 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 and lactate production but also destroyed the resistance of mice to LPS-induced sepsis initiated by transfer of bone marrow\u2013derived macrophages 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1901246","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T00:25:37Z","timestamp":1584404737000},"page":"2232-2241","source":"Crossref","is-referenced-by-count":57,"title":["Zhx2 Accelerates Sepsis by Promoting Macrophage Glycolysis via Pfkfb3"],"prefix":"10.1093","volume":"204","author":[{"given":"Zehua","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, Shandong University School of Basic Medical Sciences , Jinan, Shandong 250012 ,","place":["People\u2019s Republic of 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Teratology of Ministry of Education, Department of Histology and Embryology, Shandong University School of Basic Medical Science , Jinan, Shandong 250012 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifen","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, Shandong University School of Basic Medical Sciences , Jinan, Shandong 250012 ,","place":["People\u2019s Republic of China"]},{"name":"Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences , Jinan, Shandong 250012 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Liang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, Shandong 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