Zhx2 Accelerates Sepsis by Promoting Macrophage Glycolysis via Pfkfb3 [INNATE IMMUNITY AND INFLAMMATION]

Key Points

Abstract

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. 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-α, IL-6, and IL-1β. 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–derived 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.

Footnotes

  • This work was supported by grants from the National Science Foundation of China (Key Project 81702647 and 81830017, 81902051, 81902443, and 81972819), the National Natural Science Foundation for Outstanding Youth Fund (81425012), the National Key Research and Development Program (2018YFE0126500), the Taishan Scholarship (tspd20181201) and the Shandong Provincial Key Innovation Project (2018FYJH0503).

  • The sequences presented in this article have been submitted to the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA598552) under accession number PRJNA598552.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BMDM
    bone marrow–derived macrophage
    ChIP
    chromatin immunoprecipitation
    CLP
    cecal ligation and puncture
    2-DG
    2-deoxy-d-glucose
    ECAR
    extracellular acidification rate
    F
    forward
    Hk2
    hexokinase 2
    Mup
    major urinary protein
    Pfkfb3
    6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3
    PM
    peritoneal macrophage
    R
    reverse
    RNA-seq
    RNA sequencing
    WT
    wild-type
    Zhx2
    zinc fingers and homeoboxes 2.
  • Received October 16, 2019.
  • Accepted February 12, 2020.

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