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 5

Macrophage Trem2 deficiency exacerbates hepatocyte lipid accumulation both in vivo and in vitro.

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Macrophage Trem2 deficiency exacerbates hepatocyte lipid accumulation bo...
(A) Schematic representation of the timing strategy used to evaluate the role of KCs in NAFLD progression. n = 12 in WT CTRL group; n =5 in Trem2–/– CTRL group; n =10 in WT GdCl3 group; n =5 in Trem2–/– GdCl3 group. (B and C) Serum and liver triglyceride or cholesterol levels in response to KCs depletion. (D) Representative images of H&E- and ORO-stained liver sections. H&E reveals tissue composition and macrovesicular fat, and ORO visualizes lipid droplets. Number of hepatocytes with macrovesicular fat and percentage of ORO-positive area per HMF was determined by ImageJ from 6 fields per section. Scale bar: 100 μm. (E) ATP contents in the liver. (F and G) Representative image of ORO-stained hepatocytes after coculture with BMDMs (F). BMDMs from WT or Trem2–/– mice were cocultured with primary hepatocytes isolated from WT or Trem2–/– mice in transwell plates. Cultures were added with PA (0.5 mM) for 24 hours in serum-free conditions. Lipid accumulation in hepatocytes was determined by quantification of ORO-positive area as a percentage of whole image area by ImageJ (G). n = 9 per group. Scale bar: 50 μm. (H) ATP content in hepatocytes was quantified by luciferase assay. n = 9 per group. The data were analyzed by 1-way analysis of variance with Bonferroni corrections for multiple comparisons. All data are shown as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.