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Cited by 17Liver physiology and pathologyLiver Diseases and ImmunityDrug-Induced Hepatotoxicity and Protection

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

Shan, Shulin, Chao, Shihua, Liu, Zhidan, Wang, Shuai, Liu, Zhaoxiong, Zhang, Cuiqin, Cheng, Dong, Su, Zhenhui, Song, Fuyong·2024·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2024.05.004
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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 (CCl 4) 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 CCl 4 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 CCl 4 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.

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References 34 · Cited by 17

Research works printed but not linked: 25

  1. Paradowska-Gorycka, 2013, Structure, expression pattern and biological activity of molecular complex TREM-2/DAP12, Hum. Immunol., 74, 730, 10.1016/j.humimm.2013.02.003 · DOI · Paper page
  2. Wang, 2015, TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model, Cell, 160, 1061, 10.1016/j.cell.2015.01.049 · DOI · Paper page
  3. Kanehisa, 2017, KEGG: new perspectives on genomes, pathways, diseases and drugs, Nucleic Acids Res., 45, D353, 10.1093/nar/gkw1092 · DOI · Paper page
  4. Deczkowska, 2020, The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway, Cell, 181, 1207, 10.1016/j.cell.2020.05.003 · DOI · Paper page
  5. Sagan, 1993, On the origin of mitosing cells. 1967, J. NIH Res. Life Sci. Res. News Natl. Inst. Health Alcohol Drug Abuse Mental Health Adm., 5, 65
  6. Wiesner, 1992, Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues, Biochem. Biophys. Res. Commun., 183, 553, 10.1016/0006-291X(92)90517-O · DOI · Paper page
  7. Shan, 2023, Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis, Ecotoxicol. Environ. Saf., 264, 10.1016/j.ecoenv.2023.115409 · DOI
  8. Shan, 2022, Drp1-mediated mitochondrial fission promotes carbon tetrachloride-induced hepatic fibrogenesis in mice, Toxicol. Res., 11, 486, 10.1093/toxres/tfac027 · DOI
  9. N, 2009, Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR, Immunity, 31, 245, 10.1016/j.immuni.2009.06.018 · DOI
  10. Yoon, 2015, PPARγ activation following apoptotic cell instillation promotes resolution of lung inflammation and fibrosis via regulation of efferocytosis and proresolving cytokines, Mucosal Immunol., 8, 1031, 10.1038/mi.2014.130 · DOI · Paper page
  11. Jonsson, 2013, Variant of TREM2 associated with the risk of Alzheimer's disease, N. Engl. J. Med., 368, 107, 10.1056/NEJMoa1211103 · DOI · Paper page
  12. Perugorria, 2019, Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage, Gut, 68, 533, 10.1136/gutjnl-2017-314107 · DOI · Paper page
  13. Esparza-Baquer, 2021, TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms, Gut, 70, 1345, 10.1136/gutjnl-2019-319227 · DOI
  14. Savill, 2002, A blast from the past: clearance of apoptotic cells regulates immune responses, Nat. Rev. Immunol., 2, 965, 10.1038/nri957 · DOI
  15. Lauber, 2004, Clearance of apoptotic cells: getting rid of the corpses, Mol. Cell, 14, 277, 10.1016/S1097-2765(04)00237-0 · DOI
  16. Morioka, 2019, Living on the edge: efferocytosis at the interface of homeostasis and pathology, Immunity, 50, 1149, 10.1016/j.immuni.2019.04.018 · DOI · Paper page
  17. Arandjelovic, 2015, Phagocytosis of apoptotic cells in homeostasis, Nat. Immunol., 16, 907, 10.1038/ni.3253 · DOI · Paper page
  18. Kidani, 2012, Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity, Immunol. Rev., 249, 72, 10.1111/j.1600-065X.2012.01153.x · DOI
  19. Schulman, 2017, Liver X receptors link lipid metabolism and inflammation, FEBS Lett., 591, 2978, 10.1002/1873-3468.12702 · DOI · Paper page
  20. Zhang, 2010, Circulating mitochondrial DAMPs cause inflammatory responses to injury, Nature, 464, 104, 10.1038/nature08780 · DOI · Paper page
  21. Man, 2016, Converging roles of caspases in inflammasome activation, cell death and innate immunity, Nat. Rev. Immunol., 16, 7, 10.1038/nri.2015.7 · DOI
  22. Wallace, 2015, Mitochondrial DNA variation in human radiation and disease, Cell, 163, 33, 10.1016/j.cell.2015.08.067 · DOI
  23. Cordero, 2016, Mutation in cytochrome b gene of mitochondrial DNA in a family with fibromyalgia is associated with NLRP3-inflammasome activation, J. Med. Genet., 53, 113, 10.1136/jmedgenet-2015-103392 · DOI
  24. Lorente, 2013, Severe septic patients with mitochondrial DNA haplogroup JT show higher survival rates: a prospective, multicenter, observational study, PLoS One, 8, 10.1371/journal.pone.0073320 · DOI
  25. Rongvaux, 2014, Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA, Cell, 159, 1563, 10.1016/j.cell.2014.11.037 · DOI · Paper page

Metadata

Authors
Shan, S., Chao, S., Liu, Z., Wang, S., Liu, Z., Zhang, C., Cheng, D., Su, Z., & Song, F.
Affiliations
  • Shandong University (CN)
  • Shandong Provincial Hospital (CN)
Corresponding author
Song, Fuyong
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2024-08
Volume
220
Pages
154-165
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2024.05.004
OpenAlex
W4396661328
Cited by
17
References
34
Citations by year
2026: 10 · 2025: 7
FWCI
4.45
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (82173552)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
TREM2, liver fibrosis, mitochondrial damage-associated molecular patterns, liver necrosis, macrophage phagocytosis, M1 macrophage polarization, inflammation, carbon tetrachloride, GSK872, therapeutic target
MeSH terms
RAW 264.7 Cells, Animals, Carbon Tetrachloride, Disease Models, Animal, Humans, Inflammation, Liver Cirrhosis, Macrophages, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mitochondria, Phagocytosis, Receptors, Immunologic, Apoptosis, Mice, Knockout, Hepatocytes, Mice

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