Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Signal. 2023 Aug 8;16(797):eade0385. doi: 10.1126/scisignal.ade0385.
Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-β (transforming growth factor-β) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-β increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-β-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of , (which encodes a TGF-β receptor), and (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-β is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.
巨噬细胞代谢的改变对于维持巨噬细胞对不同刺激的激活是必需的。我们表明，细胞因子 TGF-β（转化生长因子-β）可独立于炎性细胞因子的产生来调节巨噬细胞中的糖酵解，并影响脓毒症小鼠模型中的存活。在巨噬细胞激活过程中，TGF-β增加了糖酵解酶 PFKL（磷酸果糖激酶-1 肝型）的表达和活性，并促进糖酵解，但抑制了促炎细胞因子的产生。糖酵解的增加是通过 mTOR-c-MYC 依赖性途径介导的，而细胞因子产生的抑制则归因于转录共激活因子 SMAD3 的激活和促炎转录因子 AP-1、NF-κB 和 STAT1 的活性抑制。在 LPS 诱导的内毒素血症和实验性诱导的脓毒症的小鼠中，TGF-β诱导的巨噬细胞糖酵解增强导致存活率降低，这与血液凝固增加有关。对脓毒症患者队列的分析表明，髓样细胞中 TGF-β 受体编码基因 和凝血因子编码基因 的表达与 COVID-19 疾病呈正相关。因此，这些结果表明 TGF-β 是巨噬细胞代谢的关键调节剂，可能是脓毒症患者的治疗靶点。
