{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T08:35:48Z","timestamp":1793522148433,"version":"4.5.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"35","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK137061 R01DK133930DK091183"],"award-info":[{"award-number":["R01DK137061 R01DK133930DK091183"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL147835"],"award-info":[{"award-number":["HL147835"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,27]]},"abstract":"<jats:p>\n                    While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH\/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations.\n                    <jats:italic>Trem2<\/jats:italic>\n                    is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained\n                    <jats:italic>Trem2<\/jats:italic>\n                    expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages are superior collagen degraders. Lack of TREM2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2405746121","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T13:43:41Z","timestamp":1724334221000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":153,"title":["Lipid-associated macrophages\u2019 promotion of fibrosis resolution during MASH regression requires TREM2"],"prefix":"10.1073","volume":"121","author":[{"given":"Souradipta","family":"Ganguly","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"},{"name":"Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Brin","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Center for Computational Biology and Bioinformatics, Department of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ty D.","family":"Troutman","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093"},{"name":"Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa V.","family":"Rohm","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naser","family":"Khader","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Aleman-Muench","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolism discovery, Immunometabolism, Janssen Research &amp; Development, La Jolla, CA 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7024-0833","authenticated-orcid":false,"given":"Yasuyo","family":"Sano","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolism discovery, Immunometabolism, Janssen Research &amp; Development, La Jolla, CA 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Archilei","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pejman","family":"Soroosh","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolism discovery, Immunometabolism, Janssen Research &amp; Development, La Jolla, CA 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerrold M.","family":"Olefsky","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel E.","family":"Feldstein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Kisseleva","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Loomba","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4344-3592","authenticated-orcid":false,"given":"Christopher K.","family":"Glass","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2573-525X","authenticated-orcid":false,"given":"David A.","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"},{"name":"Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debanjan","family":"Dhar","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California, San Diego, CA 92093"},{"name":"Cancer Genome and Epigenetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 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Ganguly Lipid Associated Macrophages\u2019 Promotion of Fibrosis Resolution during MASH regression requires TREM2. GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE261829. 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