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Cited by 21Immune responses and vaccinationsImmune cells in cancerLiver physiology and pathology

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Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells

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Musrati, Mohamed Amer, Stijlemans, Benoit, Azouz, Abdulkader, Kancheva, Daliya, Mesbahi, Sarah, Hadadi, Eva, Lebegge, Els, Ali, Leen, De Vlaminck, Karen, Scheyltjens, Isabelle, Vandamme, Niels, Zivalj, Maida, Assaf, Naela, Elkrim, Yvon, Ahmidi, Ilham, Huart, Camille, Lamkanfi, Mohamed, Guilliams, Martin, De Baetselier, Patrick, Goriely, Stanislas, Movahedi, Kiavash, Van Ginderachter, Jo A.·2024·Journal of Hepatology
DOI 10.1016/j.jhep.2024.07.007
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Abstract

BACKGROUND & AIMS: Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver leads to long-term alterations to the liver macrophage compartment. METHODS: We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single-cell CITE-sequencing, single-nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection. RESULTS: We show that T. brucei brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection. CONCLUSION: Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term. IMPACT AND IMPLICATIONS: Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches.

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Crossref · 10.1016/j.jhep.2024.07.007

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  • During chronic liver injury, large numbers of bone marrow monocytes are recruited to the liver, where they differentiate into MDMs, which can be found throughout the liver, including within the KC niche of the liver sinusoids.

    “However, during chronic liver injury, large numbers of bone marrow monocytes are recruited to the liver, where they differentiate into MDMs, which can be found throughout the liver, including within the KC niche of the liver sinusoids.”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [92]

  • MDMs represent a heterogeneous population that can adopt diverse functional states and fates depending on the inflammatory context, niche, and duration of injury.

    “As such, MDMs represent a heterogeneous population that can adopt diverse functional states and fates depending on the inflammatory context, niche, and duration of injury (36, 37, 92, 94, 103–106).”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [92]

  • Monocyte-derived macrophage infiltration profoundly reshapes the Kupffer cell compartment.

    “Conversely, MoMFs infiltration profoundly reshapes the KCs compartment (31, 32).”

    From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [31]

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References 53 · Cited by 21

Research works printed but not linked: 42

  1. Ginhoux, 2016, Tissue-resident macrophage ontogeny and homeostasis, Immunity, 44, 439, 10.1016/j.immuni.2016.02.024 · DOI · Paper page
  2. Guilliams, 2020, Establishment and maintenance of the macrophage niche, Immunity, 52, 434, 10.1016/j.immuni.2020.02.015 · DOI · Paper page
  3. Rua, 2019, Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity, Nat Immunol, 20, 407, 10.1038/s41590-019-0344-y · DOI · Paper page
  4. Aegerter, 2020, Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection, Nat Immunol, 21, 145, 10.1038/s41590-019-0568-x · DOI
  5. Roquilly, 2020, Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis, Nat Immunol, 21, 636, 10.1038/s41590-020-0673-x · DOI
  6. Talwani, 2011, Infectious diseases and the liver, Clin Liver Dis, 15, 111, 10.1016/j.cld.2010.09.002 · DOI
  7. Lee, 1985, Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80, J Exp Med, 161, 475, 10.1084/jem.161.3.475 · DOI
  8. Guilliams, 2022, Liver macrophages in health and disease, Immunity, 55, 1515, 10.1016/j.immuni.2022.08.002 · DOI · Paper page
  9. Benz, 2008, The stream of precursors that colonizes the thymus proceeds selectively through the early T lineage precursor stage of T cell development, J Exp Med, 205, 1187, 10.1084/jem.20072168 · DOI
  10. Srinivas, 2001, Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus, BMC Develop Biol, 1, 4, 10.1186/1471-213X-1-4 · DOI · Paper page
  11. Scott, 2016, Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells, Nat Commun, 7, 10.1038/ncomms10321 · DOI · Paper page
  12. De Vlaminck, 2022, Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation, Immunity, 55, 2085, 10.1016/j.immuni.2022.09.005 · DOI
  13. Stijlemans, 2014, MIF contributes to trypanosoma brucei associated immunopathogenicity development, PLOS Pathog, 10, 10.1371/journal.ppat.1004414 · DOI
  14. Gomez Perdiguero, 2015, Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors, Nature, 518, 547, 10.1038/nature13989 · DOI · Paper page
  15. Scott, 2018, The transcription factor ZEB2 is required to maintain the tissue-specific identities of macrophages, Immunity, 49, 312, 10.1016/j.immuni.2018.07.004 · DOI · Paper page
  16. Sierro, 2017, A liver capsular network of monocyte-derived macrophages restricts hepatic dissemination of intraperitoneal bacteria by neutrophil recruitment, Immunity, 47, 374, 10.1016/j.immuni.2017.07.018 · DOI
  17. Remmerie, 2020, Osteopontin expression identifies a subset of recruited macrophages distinct from kupffer cells in the fatty liver, Immunity, 53, 641, 10.1016/j.immuni.2020.08.004 · DOI · Paper page
  18. Seidman, 2020, Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis, Immunity, 52, 1057, 10.1016/j.immuni.2020.04.001 · DOI · Paper page
  19. van den Brink, 2017, Single-cell sequencing reveals dissociation-induced gene expression in tissue subpopulations, Nat Methods, 14, 935, 10.1038/nmeth.4437 · DOI · Paper page
  20. Kennedy, 2013, Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness), Lancet Neurol, 12, 186, 10.1016/S1474-4422(12)70296-X · DOI
  21. Li, 2023, Monocyte-derived Kupffer cells dominate in the Kupffer cell pool during liver injury, Cel Rep, 42
  22. Browaeys, 2020, NicheNet: modeling intercellular communication by linking ligands to target genes, Nat Methods, 17, 159, 10.1038/s41592-019-0667-5 · DOI · Paper page
  23. Divangahi, 2021, Trained immunity, tolerance, priming and differentiation: distinct immunological processes, Nat Immunol, 22, 2, 10.1038/s41590-020-00845-6 · DOI
  24. Wang, 2013, Target analysis by integration of transcriptome and ChIP-seq data with BETA, Nat Protoc, 8, 2502, 10.1038/nprot.2013.150 · DOI · Paper page
  25. Ostuni, 2013, Latent enhancers activated by stimulation in differentiated cells, Cell, 152, 157, 10.1016/j.cell.2012.12.018 · DOI · Paper page
  26. Langlais, 2016, The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation, J Exp Med, 213, 585, 10.1084/jem.20151764 · DOI
  27. Kim, 2016, Nuclear factor erythroid-2 like 1 (NFE2L1): structure, function and regulation, Gene, 584, 17, 10.1016/j.gene.2016.03.002 · DOI
  28. Musrati, 2023, Ontogeny, functions and reprogramming of Kupffer cells upon infectious disease, Front Immunol, 14, 10.3389/fimmu.2023.1238452 · DOI
  29. Beattie, 2016, Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions, J Hepatol, 65, 758, 10.1016/j.jhep.2016.05.037 · DOI
  30. Zigmond, 2014, Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury, J Immunol, 193, 344, 10.4049/jimmunol.1400574 · DOI
  31. Gola, 2021, Commensal-driven immune zonation of the liver promotes host defence, Nature, 589, 131, 10.1038/s41586-020-2977-2 · DOI
  32. Lee, 2010, An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells, Nat Immunol, 11, 295, 10.1038/ni.1855 · DOI
  33. Kang, 2017, Interferon-γ represses M2 gene expression in human macrophages by disassembling enhancers bound by the transcription factor MAF, Immunity, 47, 235, 10.1016/j.immuni.2017.07.017 · DOI · Paper page
  34. Askenase, 2015, Bone-marrow-resident NK cells prime monocytes for regulatory function during infection, Immunity, 42, 1130, 10.1016/j.immuni.2015.05.011 · DOI
  35. Naik, 2017, Inflammatory memory sensitizes skin epithelial stem cells to tissue damage, Nature, 550, 475, 10.1038/nature24271 · DOI · Paper page
  36. Ivashkiv, 2018, IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy, Nat Rev Immunol, 18, 545, 10.1038/s41577-018-0029-z · DOI
  37. Kamada, 2018, vol. 115, E9162
  38. Boyle, 2011, Heme induces heme oxygenase 1 via Nrf2, Arteriosclerosis, Thromb Vasc Biol, 31, 2685, 10.1161/ATVBAHA.111.225813 · DOI
  39. Netea, 2020, Defining trained immunity and its role in health and disease, Nat Rev Immunol, 20, 375, 10.1038/s41577-020-0285-6 · DOI · Paper page
  40. Moon, 2022, Detrimental effect of trypanosoma brucei brucei infection on memory B cells and host ability to recall protective B-cell responses, J Infect Dis, 226, 528, 10.1093/infdis/jiac112 · DOI
  41. De Trez, 2020, Brucei infections abrogate diverse plasma cell-mediated effector B cell responses, independently of their specificity, affinity and host genetic background, Plos Negl Trop Dis, 14, 10.1371/journal.pntd.0008358 · DOI
  42. Yao, 2018, Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity, Cell, 175, 1634, 10.1016/j.cell.2018.09.042 · DOI

Metadata

Authors
Musrati, M. A., Stijlemans, B., Azouz, A., Kancheva, D., Mesbahi, S., Hadadi, E., Lebegge, E., Ali, L., De Vlaminck, K., Scheyltjens, I., Vandamme, N., Zivalj, M., Assaf, N., Elkrim, Y., Ahmidi, I., Huart, C., Lamkanfi, M., Guilliams, M., De Baetselier, P., Goriely, S., Movahedi, K., & Van Ginderachter, J. A.
Affiliations
  • Vrije Universiteit Brussel (BE)
  • Université Libre de Bruxelles (BE)
  • VIB-UGent Center for Inflammation Research (BE)
  • Ghent University (BE)
  • Vlaams Instituut voor Biotechnologie (BE)
Corresponding author
Movahedi, Kiavash
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2024-12
Volume
81
Issue
6
Pages
1023-1039
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2024.07.007
OpenAlex
W4400521396
Cited by
21
References
53
Citations by year
2026: 9 · 2025: 11 · 2024: 1
FWCI
3.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by-nc-nd)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • Lirias (submittedVersion, cc-by-nc-nd)
Funders
  • Waalse Gewest
  • European Resuscitation Council
  • FWO (1157718N, IBOF-21-043)
  • ERDF
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
Kupffer cells, infection history, Trypanosoma brucei brucei, parasitic liver infection, trained immunity, epigenetic remodeling, chromatin landscape, monocyte-derived macrophages, macrophage ontogeny, transcriptome, bacterial infection susceptibility
MeSH terms
Epigenome, Animals, Disease Models, Animal, Kupffer Cells, Liver, Macrophages, Trypanosoma brucei brucei, Trypanosomiasis, Mice, Transcriptome

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