Both TREM2-dependent macrophages and Kupffer cells play a protective role in APAP-induced acute liver injury.

Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE

Original Publication: Amsterdam ; New York : Elsevier Science, c2001-

Kupffer Cells*/metabolism ; Kupffer Cells*/immunology ; Acetaminophen* ; Chemical and Drug Induced Liver Injury*/pathology ; Chemical and Drug Induced Liver Injury*/immunology ; Mice, Inbred C57BL* ; Receptors, Immunologic*/genetics ; Receptors, Immunologic*/metabolism ; Membrane Glycoproteins*/metabolism ; Membrane Glycoproteins*/genetics ; Mice, Knockout* ; Macrophages*/immunology ; Macrophages*/metabolism; Animals ; Mice ; Male ; Clodronic Acid/pharmacology ; Liver/pathology ; Liver/metabolism ; Liver/immunology ; Liver/drug effects ; Necroptosis ; Liposomes ; Disease Models, Animal ; Protein Kinases/metabolism ; Protein Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Signal Transduction

The inflammatory response is a significant factor in acetaminophen (APAP)-induced acute liver injury. And it can be mediated by macrophages of different origins. However, whether Kupffer cells and mononuclear-derived macrophages play an injury or protective role in APAP hepatotoxicity is still unclear. In this study, C57/BL6N mice were performed to establish the APAP acute liver injury model. Intervention experiments were also carried out using clodronate liposomes or TREM2 knockout. We found that APAP overdose triggered the activation of inflammatory factors and enhanced the expression of the RIPK1-MLKL pathway in mice's livers. Moreover, our study showed that inflammation-related protein expression was increased after clodronate liposome administration or TREM2 knockout. The RIPK1-MLKL-mediated necroptosis was also significantly activated after the elimination of Kupffer cells or the inhibition of mononuclear-derived macrophages. More importantly, clodronate liposomes treatment and TREM2 deficiency all worsen APAP-induced liver damage in mice. In conclusion, the results indicate that Kupffer cells and mononuclear macrophages play a protective role in APAP-induced liver injury by regulating necroptosis. Therefore, macrophages hold as a potential therapeutic target for APAP-induced liver damage.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)

Keywords: APAP; Inflammation; Macrophages; Necroptosis Apoptosis; TREM2

0 (Trem2 protein, mouse)
362O9ITL9D (Acetaminophen)
0 (Receptors, Immunologic)
0 (Membrane Glycoproteins)
0813BZ6866 (Clodronic Acid)
EC 2.7.- (MLKL protein, mouse)
0 (Liposomes)
EC 2.7.- (Protein Kinases)
EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)

Date Created: 20240819 Date Completed: 20240917 Latest Revision: 20241112

20241112

10.1016/j.intimp.2024.112926

39159559