2. Academic Validation
  3. TREM2 protects against inflammation by regulating the release of mito-DAMPs from hepatocytes during liver fibrosis

TREM2 protects against inflammation by regulating the release of mito-DAMPs from hepatocytes during liver fibrosis

  • Free Radic Biol Med. 2024 May 6:220:154-165. doi: 10.1016/j.freeradbiomed.2024.05.004.
Shulin Shan 1,  Shihua Chao 2,  Zhidan Liu 2,  Shuai Wang 2,  Zhaoxiong Liu 2,  Cuiqin Zhang 2,  Dong Cheng 3,  Zhenhui Su 4,  Fuyong Song 5
Affiliations

Affiliations

  • 1 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Jinan, Shandong, 250014, China.
  • 2 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China.
  • 3 Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Jinan, Shandong, 250014, China.
  • 4 Department of Pathology, Shandong Provincial Hospital, 324 Jingwu Weiqi Road, Jinan, Shandong, 250021, China.
  • 5 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China. Electronic address: fysong3707@sdu.edu.cn.
PMID: 38710340 DOI: 10.1016/j.freeradbiomed.2024.05.004
Abstract

Background: Liver fibrosis typically develops as a result of chronic liver injury, which involves inflammatory and regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressing in hepatic non-parenchymal cells, plays a crucial role in regulating the function of macrophages. However, its mechanism in liver fibrosis remains poorly defined.

Methods: Experimental liver fibrosis models in wild type and TREM2-/- mice, and in vitro studies with AML-12 cells and Raw264.7 cells were conducted. The expression of TREM2 and related molecular mechanism were evaluated by using samples from patients with liver fibrosis.

Results: We demonstrated that TREM2 was upregulated in murine model with liver fibrosis. Mice lacking TREM2 exhibited reduced phagocytosis activity in macrophages following carbon tetrachloride (CCl4) intoxication. As a result, there was an increased accumulation of necrotic apoptotic hepatocytes. Additionally, TREM2 knockout aggravated the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from dead hepatocytes during CCl4 exposure, and further promoted the occurrence of macrophage-mediated M1 polarization. Then, TREM2-/- mice showed more serious fibrosis pathological changes. In vitro, the necrotic Apoptosis inhibitor GSK872 effectively alleviated the release of mito-DAMPs in AML-12 cells after CCl4 intoxication, which confirmed that mito-DAMPs originated from dead liver cells. Moreover, direct stimulation of Raw264.7 cells by mito-DAMPs from liver tissue can induce intracellular inflammatory response. More importantly, TREM2 was elevated and inflammatory factors were markedly accumulated surrounding dead cells in the livers of human patients with liver fibrosis.

Conclusion: Our study highlights that TREM2 serves as a negative regulator of liver fibrosis, suggesting its potential as a novel therapeutic target.

Keywords

Inflammation; Liver fibrosis; Mito-DAMPs; Phagocytosis; TREM2.

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