TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis
Open accessAbstract
Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.
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Deletion 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 [19]
The Results (pp. 3, 5) report that Trem2-deficient mice developed worse high-fat-diet-induced liver steatosis, hepatocyte ballooning and inflammatory changes, supporting the worsening-disease portion of the claim. The ex vivo macrophage experiments instead examine hepatocyte lipid metabolism and exosomes (Results, pp. 7–8); no passage found in searches for efferocytosis or apoptotic-cell engulfment reports impaired efferocytosis. (LLM, conf=0.85)
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 [19]
The Results (pp. 3, 5) report that Trem2 deletion worsened liver fat accumulation, hepatocyte ballooning and inflammatory-gene expression in high-fat-diet mice, supporting an association with worsening fatty liver disease. The paper calls this a NAFLD model, however, and our copy does not report TREM2 cleavage in MASH or characterize TREM2 as an efferocytosis receptor. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe 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 [125]
The Discussion (pp. 11–12) reports that macrophage TREM2 attenuates hepatocyte lipid accumulation in a mouse NAFLD model, and the Results (p. 7) find increased expression of inflammation-linked genes in TREM2-deficient Kupffer cells. The paper does not establish dead-cell clearance, direct lipid clearance by these cells, or tissue repair, and it does not substantiate the claim about a majority of murine studies. (LLM, conf=0.86)
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 [125]
The Results (pp. 3, 7) show that Trem2 deletion worsened fat accumulation in a mouse NAFLD model and increased inflammatory gene expression in Kupffer cells. They do not show that TREM2-deficient macrophages failed to acquire reparative phenotypes, had impaired efferocytosis, or exacerbated fibrogenesis in an experimental liver-fibrosis model. (LLM, conf=0.78)
Experimental — accuracy not yet measuredTREM2 plays a protective role in steatosis.
“steatosis (13)”
From Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2 (2024) · cites this paper as [13]
Absence of TREM2 changes the exosome miRNA profile that alters macrophage-hepatocyte metabolic coordination in MAFL and sepsis.
“A recent study indicates that the absence of TREM2 changes the exosome miRNA profile that alters the macrophage–hepatocyte metabolic coordination in MAFL and sepsis (13).”
From Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2 (2024) · cites this paper as [13]
Recent evidence suggests TREM2+ macrophages may contribute to an adaptive response to metabolic injury in NASH and promote fibrosis regression.
“recent evidence suggests they may contribute to an adaptive response to metabolic injury in NASH and promote fibrosis regression (93, 94).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [93]
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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
- Hou, J., Zhang, J., Cui, P., Zhou, Y., Liu, C., Wu, X., Ji, Y., Wang, S., Cheng, B., Ye, H., Shu, L., Zhang, K., Wang, D., Xu, J., Shu, Q., Colonna, M., & Fang, X.
- Affiliations
- Washington University in St. Louis (US)
- First Affiliated Hospital Zhejiang University (CN)
- University of Maryland, Baltimore (US)
- Wannan Medical College (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Brown University (US)
- Zhejiang University (CN)
- Cleveland Clinic (US)
- Children's Hospital of Zhejiang University (CN)
- Corresponding author
- Colonna, Marco
- Fang, Xiangming
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-02-15
- Volume
- 131
- Issue
- 4
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7880419
- OpenAlex
- W3130149107
- Cited by
- 239
- References
- 53
- Citations by year
- 2026: 36 · 2025: 47 · 2024: 43 · 2023: 53 · 2022: 45 · 2021: 14 · 2014: 1
- FWCI
- 28.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- the National Key Research and Development Program of China (No: 2018YFC2001904)
- the National Natural Science Foundation of China (No. 81720108025, No. 81971865)
- the Natural Science Foundation of Zhejiang Province, China (No. LR19H150001)
- the Special Fund for Basic Scientific Research of Zhejiang University (No: 2019QNA7039)
- Washington University in St. Louis (none)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TREM2, non-alcoholic fatty liver disease, sepsis, hepatic macrophages, mitochondrial dysfunction, hepatocyte energy metabolism, exosomes, miR-106b-5p, mitofusin 2, mortality
- MeSH terms
- Animals, Cell Communication, Energy Metabolism, Female, Humans, Macrophages, Male, Membrane Glycoproteins, Mitochondria, Liver, Receptors, Immunologic, Mice, Knockout, Sepsis, GTP Phosphohydrolases, Hepatocytes, Mitochondrial Proteins, MicroRNAs, Mice, Non-alcoholic Fatty Liver Disease
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