Kupffer cell expression of macrophage receptor with collagenous structure modulates macrophage gene induction and limits acute liver injury
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Macrophages displaying a pro-repair and anti-inflammatory polarization have been implicated in resolution of acute liver injury. Macrophage receptor with collagenous structure (MARCO) expression marks tolerogenic hepatic macrophages and is expressed by pro-resolution macrophages in the injured liver. We tested the hypothesis that MARCO promotes repair of the acetaminophen (APAP)-injured liver. Robust and sustained induction of MARCO mRNA and protein expression was evident in livers of mice challenged with a hepatotoxic dose of APAP (i.e. 300 mg/kg), whereas hepatic MARCO induction failed in mice with APAP-induced liver failure (i.e. 600 mg/kg). Serum proteomics identified a significant increase in serum MARCO levels in surviving acute liver failure (ALF) patients, but not in ALF patients who died. MARCO expression was high in F480+ liver macrophages, and MARCO deficiency reduced macrophage expression of pro-resolution markers such as Gpnmb and Mertk during the repair phase (i.e. 48 h). The results suggested a delay in necrosis resolution along with a trend toward increased mortality in APAP-challenged MARCO−/− mice. Notably, a robust increase in peak hepatic injury (i.e. 6- to 24-h post-APAP challenge) was evident in MARCO−/− mice, which could not be ascribed to differences in NAPQI/APAP-adduct generation nor changes in hepatic neutrophil/macrophage numbers. Interestingly, a reduction in hepatic CD11c+ cells, shown previously to limit APAP-induced liver injury, was evident 24 h after APAP challenge in MARCO−/− mice. The results indicate that MARCO deficiency worsens APAP-induced acute liver injury in mice and provide experimental and initial translational evidence linking MARCO induction to positive outcomes in acute liver injury.
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MARCO+ macrophages may attenuate liver injury by boosting expression of pro-resolution genes (MerTK, Gpnmb) and regulating the number of CD11c+ repair cells.
“Poole et al. found that macrophage receptor with collagenous structure (MARCO)+ macrophages may attenuate liver injury by boosting the expression of pro-resolution genes (e.g., MerTK, Gpnmb) and regulating the number of CD11c+ repair cells (49).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [49]
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- Authors
- Poole, L. G., Wei, Z., Schulte, A., Cline, H. M., Bernard, M. P., Buchweitz, J. P., McGill, M. R., & Luyendyk, J. P.
- Affiliations
- Michigan State University (US)
- University of Arkansas for Medical Sciences (US)
- Corresponding author
- Luyendyk, James P
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-03-21
- Volume
- 205
- Issue
- 2
- Pages
- 417-427
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W4408745492
- Cited by
- 5
- References
- 29
- Citations by year
- 2026: 4 · 2025: 1
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 DK135649, F32DK121423, R01 DK135752)
- United States Department of Agriculture
- National Institute of Food and Agriculture
- Albert C. and Lois E. Dehn Endowment to Michigan State University for Veterinary Medicine
- Pathobiology and Diagnostic Investigation
- Michigan State University College of Natural Sciences
- Family of John A. Penner
- John A. Penner Endowed Research Fellowship
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MARCO, hepatic macrophages, Kupffer cells, acetaminophen hepatotoxicity, acute liver failure, liver repair, macrophage polarization, GPNMB, MERTK, CD11c+ cells, hepatotoxicity
- MeSH terms
- c-Mer Tyrosine Kinase, Acetaminophen, Animals, Humans, Kupffer Cells, Liver, Macrophages, Male, Mice, Inbred C57BL, Receptors, Immunologic, RNA, Messenger, Transcriptional Activation, Liver Failure, Acute, Mice, Knockout, Hepatocytes, Mice, Chemical and Drug Induced Liver Injury
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