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 6

Trem2 deletion changes macrophage-Exos numbers and contents.

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Trem2 deletion changes macrophage-Exos numbers and contents. (A) GO ana...
(A) GO analysis of DEGs in KCs from WT or Trem2–/– mice fed HFD for 8 weeks. n = 3 per group. (B) Representative TEM images of Exos from WT and Trem2–/– BMDMs incubated with PA (0.5 mM) for 12 hours. Scale bar: 100 nm. (C) Representative results of nanoparticle tracking analysis demonstrate size distribution of Exos derived from WT and Trem2–/– BMDMs. n = 5 per group. (D) WT primary hepatocytes were incubated with WT or Trem2–/– BMDM-derived Exos (20 μg/mL) and PA (0.5 mM) for 12 hours. Lipid accumulation in hepatocytes was determined by quantification of ORO-positive area as a percentage of whole image area by ImageJ. n = 16 in WT group; n = 19 in Trem2–/– group. Scale bar: 25 μm. (E) Experimental design used to evaluate BMDM-Exos in NAFLD progression. n = 6 in WT-Exos group; n = 5 in Trem2–/–-Exos group. (F) Liver weights and liver weight/body weight ratios of mice with Exos treatment. (G and H) Serum and liver triglyceride levels in response to Exos treatment. (I) Representative images of ORO-stained liver sections from mice treated with Exos from WT or Trem2–/– BMDMs. Scale bar: 100 μm. Percentage of ORO-positive area per HMF were determined by ImageJ from 6 fields per section. (J) ATP content in hepatocytes was quantified by luciferase assay. Data are presented as the mean ± SD. The data were analyzed by an unpaired, 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.