Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development
Open accessAbstract
Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.
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The majority of murine studies suggest LAMs/LAM-like KCs play a role in tissue repair, contributing to dead cell and lipid clearance, reducing lipotoxic stress, and preventing uncontrolled inflammation.
“While the majority of murine studies to date have suggested a role for LAMs/LAM-like KCs in tissue repair, contributing to dead cell and lipid clearance, thus reducing lipotoxic stress, and preventing uncontrolled inflammation (36, 108, 122–126)”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [123]
The Results and Discussion (page unavailable in our copy) show that TREM2-dependent liver macrophages clear lipid-laden apoptotic hepatocytes and restrict chronic inflammation in mice. The paper does not establish separate lipid clearance or reduced lipotoxic stress, and its Limitations section says the responsible macrophage subpopulation remains unidentified, including whether Kupffer cells contribute. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn experimental liver fibrosis in murine models, TREM2-deficient macrophages failed to acquire reparative phenotypes, showed impaired efferocytosis, and exacerbated fibrogenesis.
“However, in experimental liver fibrosis in murine models, TREM2-deficient macrophages failed to acquire reparative phenotypes, showed impaired efferocytosis, and exacerbated fibrogenesis (36, 122–126).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [123]
In Results, “Genetic ablation of Trem2 in macrophages exacerbates NASH pathology” reports increased liver fibrosis in TREM2-deficient mice fed a Western diet. Results, “TREM2 is required for macrophage-dependent efferocytosis,” reports defective engulfment of apoptotic hepatocytes. The paper does not show that these macrophages failed to acquire reparative phenotypes; its experimental setting is diet-induced NASH, rather than liver-fibrosis models generally. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDeletion of TREM2 in macrophages impairs efferocytosis ex vivo and worsens experimental MASH.
“Other groups have shown that deletion of triggering receptor expressed on myeloid cells 2 (TREM2) in macrophages impairs efferocytosis ex vivo and exacerbates experimental MASH (16–19)”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [16]
Experimental — accuracy not yet measuredAnother efferocytosis receptor, TREM2, undergoes cleavage in MASH, and genetic deletion of Trem2 in mice is associated with MASH progression.
“Another efferocytosis receptor, TREM2, undergoes cleavage in MASH (16), and genetic deletion of Trem2 in mice is associated with MASH progression (16–19).”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [16]
TREM2 plays a protective role in MASH.
“and MASH (14, 15)”
From Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2 (2024) · cites this paper as [15]
TREM2+ macrophages were shown to be efficient in efferocytosis and removal of damaged hepatocytes.
“TREM2+ macrophages were shown to be efficient in efferocytosis and removal of damaged hepatocytes (15).”
From Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2 (2024) · cites this paper as [15]
Myeloid-cell-specific deletion of Trem2 did not affect gain of liver and body weight or hepatic steatosis.
“Importantly, however, myeloid-cell-specific deletion of Trem2 (Trem2ΔMye, generated by crossing Trem2-Floxed mice with Lyz2-Cre) did not affect gain of liver and body weight or hepatic steatosis (similar to our observation) (15).”
From Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2 (2024) · cites this paper as [15]
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Regulation of liver subcellular architecture controls metabolic homeostasis
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Fractalkine-Induced MFG-E8 Leads to Enhanced Apoptotic Cell Clearance by Macrophages
Miksa, M., Amin, D., Wu, R., Dong, W., Ravikumar, T. S., & Wang, P. (2007) · Molecular Medicine · doi:10.2119/2007-00019.miksa · Cited by 118 · see citing works
Kahraman, A., Schlattjan, M., Kocabayoglu, P., Yildiz-Meziletoglu, S., Schlensak, M., Fingas, C. D., Wedemeyer, I., Marquitan, G., Gieseler, R. K. H., Baba, H. A., et al. (2009) · Hepatology · doi:10.1002/hep.23253 · Cited by 116 · see citing works
Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells
Shirotani, K., Hori, Y., Yoshizaki, R., Higuchi, E., Colonna, M., Saito, T., Hashimoto, S., Saito, T., Saido, T. C., & Iwata, N. (2019) · Scientific Reports · doi:10.1038/s41598-019-43535-6 · Cited by 116 · see citing works
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The Liver at the Nexus of Host-Microbial Interactions
Macpherson, A. J., Heikenwälder, M. F., & Ganal-Vonarburg, S. C. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.10.016 · Cited by 113 · see citing works
Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice
Locatelli, I., Sutti, S., Jindal, A., Vacchiano, M., Bozzola, C., Reutelingsperger, C. P. M., Kusters, D. H. M., Bena, S., Parola, M., Paternostro, C., et al. (2014) · Hepatology · doi:10.1002/hep.27141 · Cited by 106 · see citing works
High‐Mobility Group Box‐1 and Liver Disease
Gaskell, H., Ge, X., & Nieto, N. (2018) · Hepatology Communications · doi:10.1002/hep4.1223 · Cited by 104 · see citing works
Liao, C., Song, M. J., Gao, Y., Mauer, A. S., Revzin, A., & Malhi, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02980 · Cited by 99 · see citing works
Nadph oxidase 1 in liver macrophages promotes inflammation and tumor development in mice
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Inflammation and liver tumorigenesis
Sun, B., & Karin, M. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0256-4 · Cited by 88 · see citing works
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Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells
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Choi, Y., Abdelmegeed, M. A., & Song, B. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2017.02.039 · Cited by 81 · see citing works
Fractalkine-upregulated milk-fat globule EGF factor-8 protein in cultured rat microglia
Leonardi‐Essmann, F., Emig, M., Kitamura, Y., Spanagel, R., & Gebicke‐Haerter, P. J. (2005) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.11.012 · Cited by 72 · see citing works
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Coelho, I., Duarte, N., Barros, A., Macedo, M. P., & Penha-Gonçalves, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.616044 · Cited by 70 · see citing works
Fujiwara, N., Kobayashi, M., Fobar, A. J., Hoshida, A., Marquez, C. A., Koneru, B., Panda, G., Taguri, M., Qian, T., Raman, I., et al. (2021) · Med · doi:10.1016/j.medj.2021.03.017 · Cited by 70 · see citing works
Self-citationBellanti, F., Villani, R., Tamborra, R., Blonda, M., Iannelli, G., di Bello, G., Facciorusso, A., Poli, G., Iuliano, L., Avolio, C., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.11.016 · Cited by 70 · see citing works
Chandran, V. I., Wernberg, C. W., Lauridsen, M. M., Skytthe, M. K., Bendixen, S. M., Larsen, F. T., Hansen, C. D., Grønkjær, L. L., Siersbæk, M. S., Caterino, T. D., et al. (2022) · Hepatology · doi:10.1002/hep.32620 · Cited by 63 · see citing works
Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages
Sharif, O., Brunner, J. S., Korosec, A., Martins, R., Jaïs, A., Snijder, B., Vogel, A., Caldera, M., Hladik, A., Lakovits, K., et al. (2021) · Diabetes · doi:10.2337/db20-0572 · Cited by 60 · see citing works
Impaired phagocytic mechanism in annexin 1 null macrophages
Yona, S., Heinsbroek, S. E. M., Peiser, L., et al. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706730 · Cited by 55 · see citing works
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Exon 2‐mediated deletion of Trem2 does not worsen metabolic function in diet‐induced obese mice
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The lipid-sensor TREM2 aggravates disease in a model of LCMV-induced hepatitis
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Flagged first, then by citations
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Sorted by citations
Metabolic reprogramming in liver fibrosis
Horn, P., & Tacke, F. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.05.003 · Cited by 432 · see citing works
Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2
Ganguly, S., Rosenthal, S. B., Ishizuka, K., Troutman, T. D., Rohm, T. V., Khader, N., Aleman-Muench, G., Sano, Y., Archilei, S., Soroosh, P., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2405746121 · Cited by 145 · see citing works
“TREM2 + macrophages were shown to be efficient in efferocy-tosis and removal of damaged hepatocytes ( 15 ).”
InfluentialSpatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair
De Ponti, F. F., Bujko, A., Liu, Z., Collins, P. J., Schuermans, S., Maueroder, C., Amstelveen, S., Thoné, T., Martens, L., McKendrick, J. G., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.01.002 · Cited by 94 · see citing works
Immunopathogenic mechanisms and immunoregulatory therapies in MASLD
He, Y., Chen, Y., Qian, S., van Der Merwe, S., Dhar, D., Brenner, D. A., & Tacke, F. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01307-5 · Cited by 81 · see citing works
“Hepatocyte-derived sphingosine-1 phosphate (S1P) was also shown to induce Trem2 expression in macrophages [39].”
Liebold, I., Meyer, S., Heine, M., Kuhl, A., Witt, J., Eissing, L., Fischer, A., Koop, A., Kluwe, J., Schulze zur Wiesch, J., et al. (2023) · Cells · doi:10.3390/cells12030341 · Cited by 55 · see citing works
Liver macrophages: development, dynamics, and functions
Nusse, Y., & Kubes, P. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01298-3 · Cited by 50 · see citing works
Spatial dimension of macrophage heterogeneity in liver diseases
Guillot, A., & Tacke, F. (2023) · eGastroenterology · doi:10.1136/egastro-2023-000003 · Cited by 40 · see citing works
The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC
Wu, Q., Yang, Y., Lin, S., Geller, D. A., & Yan, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1569915 · Cited by 32 · see citing works
Efferocytosis in liver disease
Shi, H., Moore, M. P., Wang, X., & Tabas, I. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2023.100960 · Cited by 30 · see citing works
Self-citationShi, H., Wang, X., Sloas, C., Gerlach, B., Yurdagul, A., Moore, M. P., Jung, E. J., Mirshahi, F., Ronzoni, L., Sanyal, A. J., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adv2106 · Cited by 30 · see citing works
Self-citationZeng, L., Wang, Y., Huang, Y., Yang, W., Zhou, P., Wan, Y., Tao, K., & Li, R. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02075-5 · Cited by 22 · see citing works
Cao, C., Liu, W., Guo, X., Weng, S., Chen, Y., Luo, Y., Wang, S., Zhu, B., Liu, Y., & Peng, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1460431 · Cited by 16 · see citing works
Targeting macrophages in liver fibrosis
González del Barrio, L., Ipsen, D. H., Pfister, D. R., Hancz, D., & Scott, C. L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1835489 · Cited by 3 · see citing works
- Authors
- Wang, X., He, Q., Zhou, C., Xu, Y., Liu, D., Fujiwara, N., Kubota, N., Click, A., Henderson, P., Vancil, J., Marquez, C. A., Gunasekaran, G., Schwartz, M. E., Tabrizian, P., Sarpel, U., Fiel, M. I., Diao, Y., Sun, B., Hoshida, Y., Liang, S., & Zhong, Z.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Nanjing First Hospital (CN)
- Duke University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Nanjing Drum Tower Hospital (CN)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Liang, Shuang
- Zhong, Zhenyu
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 56
- Issue
- 1
- Pages
- 58-77.e11
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC9839616
- OpenAlex
- W4311468925
- Cited by
- 262
- References
- 109
- Citations by year
- 2026: 85 · 2025: 83 · 2024: 67 · 2023: 27
- FWCI
- 16.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 507 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA233794, R01CA255621)
- National Institute of General Medical Sciences (R35GM142654)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099558, P30DK127984)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- TREM2, efferocytosis, nonalcoholic steatohepatitis, chronic liver inflammation, overnutrition, obesity, macrophages, sphingosine-1-phosphate, ADAM17, TNF-α, IL-1β, hepatocyte apoptosis, non-alcoholic fatty liver disease
- MeSH terms
- Humans, Inflammation, Liver, Membrane Glycoproteins, Obesity, Receptors, Immunologic, Overnutrition, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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