TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis
Siqi Ming, … , Xi Huang, Yongjian Wu
Siqi Ming, … , Xi Huang, Yongjian Wu
Published October 15, 2024
Citation Information: J Clin Invest. 2025;135(1):e159400. https://doi.org/10.1172/JCI159400.
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Research Article Infectious disease

TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis

Abstract

Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly upregulated in sepsis patients and correlated with the severity of sepsis. Knockout of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2-knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit bruton tyrosine kinase–mediated (BTK-mediated) FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO that may provide a promising target for the clinical treatment of sepsis.

Authors

Siqi Ming, Xingyu Li, Qiang Xiao, Siying Qu, Qiaohua Wang, Qiongyan Fang, Pingping Liang, Yating Xu, Jingwen Yang, Yongqiang Yang, Xi Huang, Yongjian Wu

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Figure 1

TREM2 expression is upregulated in monocytes/macrophages and associated with disease severity in sepsis.

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TREM2 expression is upregulated in monocytes/macrophages and associated ...
(A and B) RNA-Seq of healthy controls (n = 10) and sepsis patients (n = 10) was performed. (A) Heatmap of markedly altered genes related to inflammation is shown. (B) PBMCs were isolated from healthy controls (n = 45) and sepsis patients (n = 54), respectively. TREM2 expression on CD11b+CD14+ monocytes was determined by flow cytometry. (C) CLP mouse model was established and TREM2 expression in CD11b+ F4/80+ macrophages at day 1, day 3, and day 5 after infection was assessed in PLFs, spleen, liver, and lung by flow cytometry. (D) Single-cell sequencing data from the lung of CLP sepsis mice were analyzed, and violin plots for the expression of Trem2, Ms4a3, Ms4a7, Spp1, Cd81, and Cd63 in TREM2– and TREM2+ macrophage clusters are shown. (E) The correlations of the percentages of TREM2+ monocytes with CRP, total bilirubin, BUN, and ALT levels were analyzed in sepsis patients (n = 54). (F) PBMCs were collected from sepsis patients (n = 15) on the ICU admission day (day 0) and 1, 3, 5, and 7 days after treatment. TREM2 expression on monocytes was detected and serum CRP levels were displayed. (G) The correlations of the percentages of TREM2+ monocytes with serum glucose and triglyceride concentrations were analyzed in sepsis patients (n = 54). Unpaired Student’s t test was performed (B). One-way ANOVA was employed (C and F). Spearman’s correlation analysis was used (E and G). Data are represented as means ± SEM from 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001.