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Cited by 66Liver physiology and pathologyImmune cells in cancerLiver Disease Diagnosis and Treatment

Epigenetic Regulation of Kupffer Cell Function in Health and Disease

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Bennett, Hunter, Troutman, Ty D., Sakai, Mashito, Glass, Christopher K.·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2020.609618PMC PMC7870864
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Abstract

Kupffer cells, the resident macrophages of the liver, comprise the largest pool of tissue macrophages in the body. Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They also engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. Here, we review recent studies of the epigenetic pathways that establish Kupffer cell identity and function. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

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  • SCENIC+ analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, in agreement with literature.

    “This analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, and in agreement with literature15–20.”

    From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [15]

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  • This approach identified PU.1, Runx, and Irf as candidate TFs for Kupffer cell enhancers; Pax5 and Ebf1 for B cells; Tbx21 for T cells; Meis1, Maf and Gata4 for LSECs; Mef2c and Lhx2 for HSC; and Tead4, Sox9 and Hnf1b for BECs.

    “this approach identified PU.1, Runx, and Irf as candidate TFs for Kupffer cell enhancers37; Pax5 and Ebf1 for B cells38; Tbx21 for T cells39; Meis1, Maf and Gata4 for LSECs40; Mef2c and Lhx2 for HSC41; and Tead4, Sox9 and Hnf1b for BECs42”

    From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [37]

    For the clause citing this paper, the Homeostatic Transcriptional Regulation of KC Function section says PU.1 motifs are enriched in Kupffer-cell-specific enhancers. The copy discusses IRFs as Kupffer-cell transcription factors but does not identify IRF enhancer motifs or Runx as a candidate for those enhancers. The other cell types in the sentence have separate citations and are not assessed here. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Bennett, H., Troutman, T. D., Sakai, M., & Glass, C. K.
Affiliations
University of California San Diego (US)
Corresponding author
Glass, Christopher K.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-01-26
Volume
11
Pages
609618-609618
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.609618
PMC
PMC7870864
OpenAlex
W3122351617
Cited by
66
References
24
Citations by year
2026: 9 · 2025: 12 · 2024: 10 · 2023: 19 · 2022: 13 · 2021: 3
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (DK091183, HL088083, DK063491, GM085764 , 5T32DK720243 , F30DK124980, P30DK063491, T32DK007044, T32CA009523)
  • Fondation Leducq (16CVD01)
  • Manpei Suzuki Diabetes Foundation
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
Kupffer cells, epigenetic regulation, bone marrow-derived monocytes, hepatic macrophages, iron scavenging, antigen presentation, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, liver homeostasis
MeSH terms
Animals, Bone Marrow, Cell Differentiation, Fatty Liver, Homeostasis, Humans, Kupffer Cells, Liver, Macrophages, Monocytes, Signal Transduction, Epigenesis, Genetic, Non-alcoholic Fatty Liver Disease

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