2. Academic Validation
  3. Bile acids target mitofusin 2 to differentially regulate innate immunity in physiological versus cholestatic conditions

Bile acids target mitofusin 2 to differentially regulate innate immunity in physiological versus cholestatic conditions

  • Cell Rep. 2023 Jan 31;42(1):112011. doi: 10.1016/j.celrep.2023.112011.
Yuan Che 1,  Wanfeng Xu 2,  Chujie Ding 1,  Tianyu He 1,  Xiaowei Xu 1,  Yubing Shuai 1,  Hai Huang 1,  Jiawei Wu 1,  Yun Wang 1,  Chen Wang 3,  Guangji Wang 4,  Lijuan Cao 5,  Haiping Hao 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacy, The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, Shenzhen 518001, China.
  • 3 State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
  • 4 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing 210009, China.
  • 5 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: caolijuan0702@cpu.edu.cn.
  • 6 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haipinghao@cpu.edu.cn.
PMID: 36656708 DOI: 10.1016/j.celrep.2023.112011
Abstract

Systemic metabolites serving as danger-associated molecular patterns play crucial roles in modulating the development, differentiation, and activity of innate immune cells. Yet, it is unclear how innate immune cells detect systemic metabolites for signal transmission. Here, we show that bile acids function as endogenous mitofusin 2 (MFN2) ligands and differentially modulate innate immune response to Bacterial infection under cholestatic and physiological conditions. Bile acids at high concentrations promote mitochondrial tethering to the endoplasmic reticulum (ER), leading to calcium overload in the mitochondrion, which activates NLRP3 inflammasome and Pyroptosis. By contrast, at physiologically relevant low concentrations, bile acids promote mitochondrial fusion, leading to enhanced Oxidative Phosphorylation and thereby strengthening infiltrated macrophages mediated phagocytotic clearance of bacteria. These findings support that bile acids, as endogenous activators of MFN2, are vital for tuning innate immune responses against infections, representing a causal link that connects systemic metabolism with mitochondrial dynamics in shaping innate immunity.

Keywords

Bile acids; CP: Metabolism; CP: Molecular biology; Infection; Macrophage; Metabolism; Mitochondrion; Mitofusin 2.

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