TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis
Jinchao Hou, … , Marco Colonna, Xiangming Fang
Jinchao Hou, … , Marco Colonna, Xiangming Fang
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e135197. https://doi.org/10.1172/JCI135197.
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Research Article Hepatology Metabolism

TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis

Abstract

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.

Authors

Jinchao Hou, Jue Zhang, Ping Cui, Yingyue Zhou, Can Liu, Xiaoliang Wu, Yun Ji, Sicong Wang, Baoli Cheng, Hui Ye, Liqi Shu, Kai Zhang, Di Wang, Jielin Xu, Qiang Shu, Marco Colonna, Xiangming Fang

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Figure 8

Trem2 deficiency increases susceptibility to NAFLD-associated sepsis.

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Trem2 deficiency increases susceptibility to NAFLD-associated sepsis. (...
(A) Experimental design used to set up NAFLD and sepsis. (B) WT and Trem2–/– mice fed NCD or HFD for 8 weeks were subjected to lethal CLP with an 18-gauge needle, and mice survival was monitored every 12 hours. n = 10 for NCD WT mice; n = 11 for NCD Trem2–/– mice; n = 11 for HFD WT mice; n = 13 for HFD Trem2–/– mice. (C) Blood bacterial burden at 24 hours post-CLP. n = 5 for NCD WT mice; n = 6 for NCD Trem2–/– mice; n = 4 for HFD WT mice; n = 6 for HFD Trem2–/– mice. (D) Plasma cytokine markers were quantified 24 hours after CLP. n = 5 per group. (E) Representative TEM images of mouse hepatocellular mitochondria obtained from WT or Trem2–/– mice livers 24 hours after CLP. n = 2–6 for each group. Scale bar: 1 μm. (F) Levels of ATP contents in livers from WT or Trem2–/– mice at 24 hours after CLP. n = 7 in WT NCD group; n = 8 in Trem2–/– NCD group; n = 6 in WT HFD group; n = 9 in Trem2–/– HFD group. Data are presented as the mean ± SD. Data were analyzed by 1-way analysis of variance with Bonferroni corrections for multiple comparisons (C, D, and F). The survival rates were analyzed by log-rank test (B). *P < 0.05, **P < 0.01, ***P < 0.001.