PMID- 37688662 OWN - NLM STAT- MEDLINE DCOM- 20230911 LR - 20231013 IS - 1420-9071 (Electronic) IS - 1420-682X (Print) IS - 1420-682X (Linking) VI - 80 IP - 10 DP - 2023 Sep 9 TI - Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming. PG - 283 LID - 10.1007/s00018-023-04932-3 [doi] LID - 283 AB - 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-alpha and IFN-gamma), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (T(reg)) 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. CI - (c) 2023. The Author(s). FAU - Liu, Xianmei AU - Liu X AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. AD - Department of Interventional Radiology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People's Republic of China. FAU - Yu, Peng AU - Yu P AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Xu, Yujun AU - Xu Y AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Wang, Yun AU - Wang Y AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Chen, Jin AU - Chen J AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Tang, Fuzhou AU - Tang F AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Hu, Zuquan AU - Hu Z AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. AD - Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China. AD - State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, People's Republic of China. FAU - Zhou, Jing AU - Zhou J AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Liu, Lina AU - Liu L AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Qiu, Wei AU - Qiu W AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Ye, Yuannong AU - Ye Y AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Jia, Yi AU - Jia Y AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. AD - 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. FAU - Yao, Weijuan AU - Yao W AD - 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. FAU - Long, Jinhua AU - Long J AD - Department of Head & Neck, Affiliated Tumor Hospital of Guizhou Medical University, Guiyang, 550004, People's Republic of China. longjinhua100@sina.cn. FAU - Zeng, Zhu AU - Zeng Z AUID- ORCID: 0000-0003-1989-5142 AD - School of Basic Medical Sciences/School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People's Republic of China. zengzhu@gmc.edu.cn. AD - 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. AD - 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. AD - State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, People's Republic of China. zengzhu@gmc.edu.cn. LA - eng GR - 12132006/National Natural Science Foundation of China/ GR - 31771014/National Natural Science Foundation of China/ GR - 32171143/National Natural Science Foundation of China/ GR - 11732001/National Natural Science Foundation of China/ GR - 82060555/National Natural Science Foundation of China/ GR - 31860262/National Natural Science Foundation of China/ GR - 2018-1412/Natural Science Foundation of Guizhou Province/ GR - [2023]402/Guizhou Provincial Basic Research Program (Natural Science), china/ GR - YJSCXJH 2019-068/Natural Science Research Project of Education Department of Guizhou Province, china/ GR - gyfybsky-2023-04/Doctor Start-up Fund of Affiliated Hospital of Guizhou Medical University, China/ PT - Journal Article DEP - 20230909 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - 9100L32L2N (Metformin) RN - 0 (Fatty Acids) SB - IM MH - Humans MH - *Metformin/pharmacology MH - Lipid Metabolism MH - Citric Acid Cycle MH - *Autoimmune Diseases MH - Fatty Acids MH - Dendritic Cells PMC - PMC10492886 OTO - NOTNLM OT - Autoimmune diseases OT - Dendritic cells OT - Immune metabolism OT - Immune tolerance OT - Metformin OT - Tolerant dendritic cells COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/09/09 21:43 MHDA- 2023/09/11 06:42 PMCR- 2023/09/09 CRDT- 2023/09/09 11:07 PHST- 2023/05/25 00:00 [received] PHST- 2023/08/21 00:00 [accepted] PHST- 2023/08/13 00:00 [revised] PHST- 2023/09/11 06:42 [medline] PHST- 2023/09/09 21:43 [pubmed] PHST- 2023/09/09 11:07 [entrez] PHST- 2023/09/09 00:00 [pmc-release] AID - 10.1007/s00018-023-04932-3 [pii] AID - 4932 [pii] AID - 10.1007/s00018-023-04932-3 [doi] PST - epublish SO - Cell Mol Life Sci. 2023 Sep 9;80(10):283. doi: 10.1007/s00018-023-04932-3.