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 4

Inhibition of FAO abolishes the improved sepsis symptoms regulated by TREM2.

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Inhibition of FAO abolishes the improved sepsis symptoms regulated by TR...
(A–C) CPTIfl/fl and CPTIfl/flLyz2Cre mice were treated with anti-TREM2 blocking Ab (150mg/kg) or IgG isotype control for 2 hours, followed by the establishment of CLP model. (A) The survival rates were observed. (B) IL-1β, IL-6, and TNF-α levels in serum were determined by ELISA at 24 hours after CLP challenge. (C) The serum biochemical indexes including ALT, CREA2, and BUN were detected 24 hours later. (D–H) CLP model was established in TREM2fl/flLyzCre, CPTIfl/flLyz2Cre, CPTIfl/flTREM2fl/flLyz2Cre, and LyzCre control mice respectively. (D) The survival rates were observed. (E) H&E staining was performed to assess the lung injuries and inflammatory cell infiltration 24 hours later. (F) Lipid droplets in liver were assessed by oil red O staining 24 hours later. (G) Serum IL-1β, IL-6, and TNF-α levels were detected by ELISA 24 hours later. (H) ALT, BUN, and CREA2 concentrations in serum were detected 24 hours later. Log rank (Mantel-Cox) test was adopted to compare significance (A and D). One-way ANOVA was employed (B, C and E–H). Data are represented as means ± SEM from at least 3 independent experiments. Scale bars: 50 μm. *P < 0.05; **P < 0.01; ***P < 0.001.