TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis
Siqi Ming, Xingyu Li, Qiang Xiao, Siying Qu, Qiaohua Wang, Qiongyan Fang, Pingping Liang, Yating Xu, Jingwen Yang, Yongqiang Yang, Xi Huang, Yongjian Wu
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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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 5

TREM2 regulates macrophage FAO through BTK kinase.

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TREM2 regulates macrophage FAO through BTK kinase. (A and B) WT and TREM...
(A and B) WT and TREM2–/– pMφ was stimulated with LPS (1 μg/ml) for indicated times. (A) The expressions of CPTI, HK2, and PKM2 were detected by Western blot. (B) The expressions of FAO-related regulators were determined by Western blot. (C) Phosphorylation and total levels of AMPKα were determined. (D) Phosphorylation and total levels of BTK and STAT6 were compared among groups by Western blot. (E and F) WT and TREM2–/– pMφ cells were treated with BTK inhibitor LFM-A13 (1 μM) or ibrutinib (1 μM) for 1 hour, followed by stimulation with LPS (1 μg/ml) for 12 hours. (E) The expressions of FAO rate-limiting enzyme CPTI and associated molecules PGC-1, as well as the phosphorylation and total levels of AMPKα and STAT6, were measured. (F) The FAO rate was determined. (G) WT and TREM2–/– BMDM cells were treated with LFM-A13 (1 μM) or ibrutinib (1 μM) for 1 hour. Then LPS (1 μg/ml) was added for additional stimulation for 12 hours. The FAO rate was tested by Seahorse XF Extracellular Flux Analyzers. (H) WT and TREM2–/– pMφ cells were pretreated with LFM-A13 or ibrutinib for 1 hour and stimulated with LPS for 12 hours. Relative mRNA expressions of IL-1β and IL-6 were detected by quantitative real-time PCR. Two-way ANOVA was used to analyze significance (F and G). One-way ANOVA was employed (H). Data are represented as means ± SEM from at least 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001.