2. Academic Validation
  3. Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming

Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming

  • Cell Mol Life Sci. 2023 Sep 9;80(10):283. doi: 10.1007/s00018-023-04932-3.
Xianmei Liu 1 2 3,  Peng Yu 1 2,  Yujun Xu 1 2,  Yun Wang 1 2,  Jin Chen 1 2,  Fuzhou Tang 1 2,  Zuquan Hu 1 2 4 5,  Jing Zhou 1 2,  Lina Liu 1 2,  Wei Qiu 1 2,  Yuannong Ye 1 2,  Yi Jia 1 2,  Weijuan Yao 6,  Jinhua Long 7,  Zhu Zeng 8 9 10 11
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China.
  • 2 Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province/Engineering Center of Cellular Immunotherapy in Guizhou Province, Guiyang, 550025, People's Republic of China.
  • 3 Department of Interventional Radiology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People's Republic of China.
  • 4 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China.
  • 5 State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, People's Republic of China.
  • 6 Hemorheology Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People's Republic of China. weijuanyao@bjmu.edu.cn.
  • 7 Department of Head & Neck, Affiliated Tumor Hospital of Guizhou Medical University, Guiyang, 550004, People's Republic of China. longjinhua100@sina.cn.
  • 8 School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. zengzhu@gmc.edu.cn.
  • 9 Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province/Engineering Center of Cellular Immunotherapy in Guizhou Province, Guiyang, 550025, People's Republic of China. zengzhu@gmc.edu.cn.
  • 10 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China. zengzhu@gmc.edu.cn.
  • 11 State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, People's Republic of China. zengzhu@gmc.edu.cn.
PMID: 37688662 DOI: 10.1007/s00018-023-04932-3
Abstract

Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs' immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Keywords

Autoimmune diseases; Dendritic cells; Immune metabolism; Immune tolerance; Metformin; Tolerant dendritic cells.

Figures
Products