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Letter to the EditorInfectious disease
Open Access | 
10.1172/JCI188895
The role of TREM2 in sepsis
Jiejie Zhu,1 Tianyin Sun,2 and Hanren Dai2
1Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, China.
2School of Pharmacy, Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
Address correspondence to: Hanren Dai, Anhui Medical University, Hefei, Anhui Province, China. Email: daihanren@126.com.
Find articles by Zhu, J. in: PubMed | Google Scholar
1Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, China.
2School of Pharmacy, Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
Address correspondence to: Hanren Dai, Anhui Medical University, Hefei, Anhui Province, China. Email: daihanren@126.com.
Find articles by Sun, T. in: PubMed | Google Scholar
1Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, China.
2School of Pharmacy, Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
Address correspondence to: Hanren Dai, Anhui Medical University, Hefei, Anhui Province, China. Email: daihanren@126.com.
Find articles by Dai, H. in: PubMed | Google Scholar
Published February 17, 2025 - More info
J Clin Invest. 2025;135(4):e188895. https://doi.org/10.1172/JCI188895.
© 2025 Zhu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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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
Abstract
Authors
Siqi Ming, Xingyu Li, Jingxian Shu, Xi Huang, Yongjian Wu
To the editor: Sepsis is a major health problem that is characterized by a documented infection and systemic inflammatory response (1). We read with great interest the recent article by Ming et al. (2), wherein the authors revealed the role of TREM2 in aggravating sepsis by inhibiting fatty acid oxidation, which may provide a therapeutic target for sepsis manipulation. In this study, Ming et al. used wild-type (WT) and TREM2-knockout (TREM2–/–) mice to establish mouse models of sepsis induced by cecal ligation and puncture (CLP). The authors found that TREM2 knockout improved the survival rates and reduced the levels of inflammation and organ injuries in the CLP model.
However, we have some concerns about their data and conclusions. We found that their findings were contradictory to the study by Zhang et al. published in Nature Metabolism (3). Zhang et al. also employed WT and TREM2−/− mice to establish a CLP-induced mouse model of sepsis. The TREM2−/− mice used in these two studies were both provided by Prof. Marco Colonna (Washington University, St. Louis, Missouri, USA). Zhang et al. analyzed the survival of WT (n = 18) and TREM2−/− (n = 30) mice after CLP, and found that the mortality of TREM2−/− septic mice was notably increased and the levels of proinflammatory mediators were higher after CLP. However, we could not ascertain the number of surviving mice reported by Ming et al., and all the WT mice were apparently dead 72 hours after CLP challenge. Moreover, experiments detecting lung injuries and inflammatory cell infiltration were focused on a limited number (n = 5) of animals in each group, while the research by Zhang et al. was based on a larger number of mice.
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