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Cited by 12Immune responses and vaccinationsBlood Coagulation and Thrombosis MechanismsImmune Response and Inflammation

Trained Immunity Causes Myeloid Cell Hypercoagulability

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Rehill, Aisling M., McCluskey, Seán, Ledwith, Anna E., Ryan, Tristram A. J., Ünlü, Betül, Leon, Gemma, Charles-Messance, Hugo, Gilbert, Edmund H. +10 more·2025·Science Advances
DOI 10.1126/sciadv.ads0105PMC PMC11887800

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Abstract

The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell “trained immunity” describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation of macrophages trained previously with β-glucan or heme exhibited significantly enhanced procoagulant activity compared to macrophages stimulated with LPS alone, which was mediated by enhanced acid sphingomyelinase–mediated tissue factor decryption. Furthermore, splenic monocytes isolated from β-glucan–trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Moreover, hematopoietic progenitor cells and bone marrow interstitial fluid from β-glucan–trained mice had enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent an opportunity for targeted intervention in immunothrombotic disease development.

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  • Modulation of transcription factors can influence unintended downstream pathways, leading to alteration of metabolism and/or systemic immune responses.

    “the modulation of transcription factors can influence unintended other downstream pathways, leading to alteration of metabolism and/or systemic immune responses”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [74]

    The Discussion (page unavailable) says β-glucan increases expression of the transcription factor EGR1 and that EGR1 regulates pro-inflammatory genes and likely contributes to coagulation-related gene programs. It also describes an inadvertent prothrombotic consequence of trained immunity. The paper does not establish that modulation of transcription factors causes the metabolic changes it describes or alters systemic immune responses. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Systemic modulation of microglial transcription factors risks disrupting peripheral immunity.

    “systemic modulation risks disrupting peripheral immunity”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [74]

    The Introduction and Discussion describe how β-glucan-induced trained immunity changes peripheral myeloid cells, but they do not address systemic modulation of microglial transcription factors or its effects on peripheral immunity. Searches for microglial transcription factors, systemic targeting, and peripheral immune effects found no passage addressing that risk. The indexed passages provide no page numbers. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • Microglial transcription factors are broadly expressed across myeloid lineages.

    “these transcription factors are broadly expressed across myeloid lineages”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [74]

    The Results and Discussion identify EGR transcription factors in macrophages and discuss their regulation of myeloid-cell genes, but do not identify them as microglial transcription factors or assess their expression across myeloid lineages. Searches for microglial transcription factors and expression across myeloid cell types found no passage addressing that claim; page numbers were unavailable in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Authors
Rehill, A. M., McCluskey, S., Ledwith, A. E., Ryan, T. A. J., Ünlü, B., Leon, G., Charles-Messance, H., Gilbert, E. H., Klavina, P., Day, E. A., Coppinger, J., O’Sullivan, J. M., McMahon, C., O’Donnell, J. S., Curtis, A. M., O’Neill, L. A. J., Sheedy, F. J., & Preston, R. J. S.
Affiliations
  • Royal College of Surgeons in Ireland (IE)
  • Trinity College Dublin (IE)
  • Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
  • School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
  • Children's Health Ireland at Crumlin (IE)
Corresponding author
Preston, Roger J. S.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-03-07
Volume
11
Issue
10
Pages
eads0105-eads0105
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.ads0105
PMC
PMC11887800
OpenAlex
W4408236157
Cited by
12
References
6
Citations by year
2026: 8 · 2025: 4
FWCI
4.44
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Children's Research Centre
  • Science Foundation Ireland (21/FFP-A/8859)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
trained immunity, procoagulant activity, tissue factor, acid sphingomyelinase, lipopolysaccharide, β-glucan, heme, macrophages, monocytes, hematopoietic progenitor cells, bone marrow, thrombosis, inflammatory diseases
MeSH terms
Trained Immunity, Animals, Blood Coagulation, Heme, Immunity, Innate, Immunologic Memory, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Monocytes, Thromboplastin, Thrombosis, Thrombophilia, Myeloid Cells, beta-Glucans, Mice

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