Gut bacterial L-lysine alters metabolism and histone methylation to drive dendritic cell tolerance
Qiang Tang,
Guangyue Fan,
Xianping Peng,
Xinyu Sun,
Xueting Kong,
Lisong Zhang,
Chunze Zhang,
Yandi Liu,
Jianming Yang,
Kaiyuan Yu,
Chunhui Miao,
Zhi Yao,
Long Li,
Zhi-Song Zhang,
Quan Wang
Affiliations
Qiang Tang
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Guangyue Fan
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Xianping Peng
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Xinyu Sun
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Xueting Kong
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Lisong Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
Chunze Zhang
Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin Institute of Coloproctology, Tianjin 300121, China
Yandi Liu
Tianjin Union Medical Center, Tianjin 300121, China
Jianming Yang
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Kaiyuan Yu
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Chunhui Miao
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Zhi Yao
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Long Li
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Corresponding author
Zhi-Song Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; Corresponding author
Quan Wang
Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Corresponding author
Summary: Dendritic cells (DCs) are responsible for maintaining tolerance to harmless antigens in the gut; however, the mechanism by which bacterial metabolites induce DC tolerance remains to be studied. Here, we observed that gut commensal bacterium-derived L-lysine stimulated the serine, glycine, one-carbon (SGOC) metabolism through the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-coenzyme A (AcCoA)-mechanistic target of rapamycin (mTOR) axis in DCs. This activation led to an increase in S-adenosyl methionine (SAM) and disruptor of telomeric silencing 1-like (DOT1L) expression, resulting in enhanced dimethylation on H3 lysine 79 (H3K79me2) enrichment at Tgfb and signal transducers and activator of transcription 3 (Stat3) gene promoters, which promote immune tolerance characteristics in DCs. The lysine-induced DC tolerance in restoring homeostasis was demonstrated using mouse models of immune-inflammatory diseases and phosphoglycerate dehydrogenase (Phgdh) conditional knockout mice. The single-cell RNA sequencing (scRNA-seq) analysis revealed that L-lysine restored homeostasis during inflammatory disorders by switching DCs to a tolerance state in vivo. Moreover, the enzyme by which bacteria effectively produce L-lysine is identified. The study reveals an unknown mechanism for regulating immune homeostasis through the intricate interplay of bacterial L-lysine, SGOC metabolism, histone methylation, and DC tolerance.
