PMID- 36766683 OWN - NLM STAT- MEDLINE DCOM- 20230214 LR - 20230220 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 12 IP - 3 DP - 2023 Jan 17 TI - TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD. LID - 10.3390/cells12030341 [doi] LID - 341 AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2(+) macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2(+) macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis. FAU - Liebold, Imke AU - Liebold I AUID- ORCID: 0000-0002-9708-4735 AD - I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. AD - Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany. FAU - Meyer, Simon AU - Meyer S AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Heine, Markus AU - Heine M AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Kuhl, Anastasia AU - Kuhl A AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Witt, Jennifer AU - Witt J AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Eissing, Leah AU - Eissing L AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Fischer, Alexander W AU - Fischer AW AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. AD - Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA. AD - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Koop, Anja Christina AU - Koop AC AD - I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Kluwe, Johannes AU - Kluwe J AD - I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. AD - Department of Internal Medicine and Gastroenterology, Amalie Sieveking Hospital, 22359 Hamburg, Germany. FAU - Wiesch, Julian Schulze Zur AU - Wiesch JSZ AD - I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Wehmeyer, Malte AU - Wehmeyer M AD - I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Knippschild, Uwe AU - Knippschild U AUID- ORCID: 0000-0001-9140-346X AD - Department of General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany. FAU - Scheja, Ludger AU - Scheja L AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Heeren, Joerg AU - Heeren J AUID- ORCID: 0000-0002-5647-1034 AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. FAU - Bosurgi, Lidia AU - Bosurgi L AUID- ORCID: 0000-0002-8775-4950 AD - I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. AD - Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany. FAU - Worthmann, Anna AU - Worthmann A AD - Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230117 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (TREM2 protein, human) RN - 0 (Membrane Glycoproteins) RN - 0 (Receptors, Immunologic) RN - 0 (Trem2 protein, mouse) SB - IM MH - Humans MH - Mice MH - Animals MH - *Non-alcoholic Fatty Liver Disease/metabolism MH - Liver Cirrhosis/pathology MH - Macrophages/metabolism MH - Apoptosis MH - Membrane Glycoproteins/genetics MH - Receptors, Immunologic PMC - PMC9913311 OTO - NOTNLM OT - TREM2 OT - fibrosis OT - inflammation OT - lipoproteins OT - macrophages OT - metabolic-associated fatty liver disease (MAFLD) OT - nonalcoholic fatty liver disease (NAFLD) OT - nonalcoholic steatohepatitis (NASH) OT - phagocytosis COIS- The authors declare no conflict of interest. EDAT- 2023/02/12 06:00 MHDA- 2023/02/15 06:00 PMCR- 2023/01/17 CRDT- 2023/02/11 01:09 PHST- 2022/12/15 00:00 [received] PHST- 2023/01/09 00:00 [revised] PHST- 2023/01/13 00:00 [accepted] PHST- 2023/02/11 01:09 [entrez] PHST- 2023/02/12 06:00 [pubmed] PHST- 2023/02/15 06:00 [medline] PHST- 2023/01/17 00:00 [pmc-release] AID - cells12030341 [pii] AID - cells-12-00341 [pii] AID - 10.3390/cells12030341 [doi] PST - epublish SO - Cells. 2023 Jan 17;12(3):341. doi: 10.3390/cells12030341.