2. Academic Validation
  3. rTM reprograms macrophages via the HIF-1α/METTL3/PFKM axis to protect mice against sepsis

rTM reprograms macrophages via the HIF-1α/METTL3/PFKM axis to protect mice against sepsis

  • Cell Mol Life Sci. 2024 Nov 16;81(1):456. doi: 10.1007/s00018-024-05489-5.
Chen Yao # 1,  Hanyong Zhu # 1,  Binbin Ji 1,  Hui Guo 1,  Zimeng Liu 2,  Ni Yang 2,  Qi Zhang 2,  Kangning Hai 2,  Chenbo Gao 2,  Jie Zhao 1,  Xueqin Li 1,  Rongqing Li 3,  Xin Chen 4,  Fandong Meng 5,  Xiucheng Pan 6,  Chunling Fu 7,  Wanpeng Cheng 1,  Fuxing Dong 8,  Jing Yang 9 10,  Yuchen Pan 11 12,  Takayuki Ikezoe 13
Affiliations

Affiliations

  • 1 Jiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 2 National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 3 Department of Medical Genetics and Prenatal Diagnosis, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225399, Jiangsu, China.
  • 4 Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 310058, Zhejiang, China.
  • 5 Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 6 Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 7 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 8 Public Experimental Research Center, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 9 Jiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. jingyang@xzhmu.edu.cn.
  • 10 National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. jingyang@xzhmu.edu.cn.
  • 11 Jiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. panyuchen@xzhmu.edu.cn.
  • 12 National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. panyuchen@xzhmu.edu.cn.
  • 13 Department of Hematology, Fukushima Medical University, Fukushima, 960-1296, Japan.
  • # Contributed equally.
PMID: 39549085 DOI: 10.1007/s00018-024-05489-5
Abstract

The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting Enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with Other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m6A level on Pfkm, and upregulated the protein expression of PFKM. METTL3 silence attenuated HIF-1α-mediated PFKM expression. These findings provide insight into the underlying mechanism of macrophage reprogramming for the treatment of sepsis.

Keywords

6-phosphofructokinase; Glycolysis; Macrophages; Methyltransferase-like 3 (METTL3); Muscle type (PFKM); Sepsis; Thrombomodulin.

Figures
Products
Inhibitors & Agonists
Other Products