MYC-mediated early glycolysis negatively regulates proinflammatory responses by controlling IRF4 in inflammatory macrophages.
MYC-mediated early glycolysis negatively regulates proinflammatory responses by controlling IRF4 in inflammatory macrophages.
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DOI：
10.1016/j.celrep.2021.109264
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发表时间：
2021-06-15
期刊：
影响因子：
8.8
通讯作者：
Park-Min KH
中科院分区：
文献类型：
--
作者：
Bae S;Park PSU;Lee Y;Mun SH;Giannopoulou E;Fujii T;Lee KP;Violante SN;Cross JR;Park-Min KH
MYC以细胞类型和细胞状态依赖的方式激活不同的代谢程序。然而，MYC在炎性巨噬细胞中的作用尚未确定。代谢和分子分析表明，MYC，而不是缺氧诱导因子1（HIF 1），参与增强炎症巨噬细胞极化过程中的早期糖酵解通量。MYC的消融通过调节乳酸脱氢酶（LDH）活性减少乳酸产生，并通过调节干扰素调节因子4（IRF 4）响应脂多糖而引起炎性细胞因子增加。此外，MYC的骨髓特异性缺失和MYC/LDH轴的药理学抑制增强体内炎症和细菌清除。这些结果阐明了MYC/LDH/IRF 4轴通过将早期糖酵解与炎症反应联系起来而在炎性巨噬细胞中的潜在作用，并表明调节由MYC/LDH轴介导的早期糖酵解通量可用于为治疗性调节巨噬细胞极化以对抗细菌感染开辟途径。MYC调节代谢和细胞功能的差异取决于细胞类型。Bae等人将MYC确定为炎症巨噬细胞中早期糖酵解的关键调节因子。MYC通过调节乳酸形成将代谢重编程与炎性巨噬细胞的功能联系起来，乳酸形成抑制IRF 4表达以微调炎性细胞因子的产生。
MYC activates different metabolic programs in a cell-type- and cell-status-dependent manner. However, the role of MYC in inflammatory macrophages has not yet been determined. Metabolic and molecular analyses reveal that MYC, but not hypoxia inducible factor 1 (HIF1), is involved in enhancing early glycolytic flux during inflammatory macrophage polarization. Ablation of MYC decreases lactate production by regulating lactate dehydrogenase (LDH) activity and causes increased inflammatory cytokines by regulating interferon regulatory factor 4 (IRF4) in response to lipopolysaccharide. Moreover, myeloid-specific deletion of MYC and pharmacological inhibition of the MYC/LDH axis enhance inflammation and the bacterial clearance in vivo. These results elucidate the potential role of the MYC/LDH/IRF4 axis in inflammatory macrophages by connecting early glycolysis with inflammatory responses and suggest that modulating early glycolytic flux mediated by the MYC/LDH axis can be used to open avenues for the therapeutic modulation of macrophage polarization to fight against bacterial infection. MYC regulates metabolism and cellular function differentially depending on cell types. Bae et al. identify MYC as a key regulator for the early glycolysis in inflammatory macrophages. MYC links metabolic reprogramming to the function of inflammatory macrophages by regulating lactate formation, which suppresses IRF4 expression to fine-tune inflammatory cytokine production.
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