OC 10.2 - A novel role for itaconate in trained immunity and myeloid cell-mediated hypercoagulability

Saturday, June 22, 2024

13:15 – 13:30 ICT

Room: 209 A-D

Presenting Author(s)

Aisling M. Rehill, BEng MSc PhD

Postdoctoral Researcher
Irish Centre for Vascular Biology,School of Pharmacy and Biomolecular Sciences,RCSI University of Medicine and Health Sciences, Dublin, Ireland
Dublin, Dublin, Ireland

Co-Author(s)

Gemma Leon, MSc PhD

Post Doctoral Researcher
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
Dublin, Dublin, Ireland
Tristram AJ Ryan

Postdoctoral Researcher
School of Biochemistry and Immunology, Trinity College Dublin, Ireland
Dublin, Dublin, Ireland
AL

Anna E. Ledwith

PhD student
3School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
Dublin, Dublin, Ireland
ED

Emily A. Day

Postdoctoral Researcher
3School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
Dublin, Dublin, Ireland
CM

Corrina McMahon

Professor
2National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
Dublin, Dublin, Ireland
JO

James S. O'Donnell

Professor of Vascular Biology
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Dublin, Dublin, Ireland
AC

Annie M. Curtis

Professor
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
Dublin, Dublin, Ireland
LO

Luke AJ O'Neill

Professor
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
Dublin, Dublin, Ireland
FS

Frederick J. Sheedy

Associate Professor
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
Dublin, Dublin, Ireland
Roger J.S. Preston

Senior Lecturer
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
Dublin, Dublin, Ireland

Background: The mechanisms underlying the increased risk of venous thromboembolism in many patients with chronic inflammatory diseases remain poorly understood. Myeloid cell ‘trained immunity’ describes long-term innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to enhanced subsequent immune response and hypercoagulability. Metabolic reprogramming is a hallmark of trained immunity required to sustain long-term transcriptomic and epigenomic changes necessary for innate immune cell memory. Itaconate is a product of the TCA cycle intermediate cis-aconitate with broad immunomodulatory activities.

Aims: To determine whether itaconate contributes to myeloid cell trained immunity and hypercoagulability.

Methods: Murine bone marrow-derived macrophages were trained with β-glucan, washed, and left for 7 days before lipopolysaccharide (LPS) re-stimulation. In vivo trained immunity was achieved by i.p. β-glucan administration.

Results: Macrophages from mice deficient in the enzyme necessary for itaconate production (ACOD1-/-) could not be ‘trained’ with β-glucan and exhibited significantly reduced proinflammatory activity compared to wild-type mice upon LPS re-stimulation. In parallel, ACOD1-/- cells were defective in supporting plasma thrombin generation compared to wild-type macrophages. β-glucan-trained macrophage-dependent thrombin generation on ACOD1-/- macrophages displayed prolonged lagtime compared to wild-type macrophages.

To assess itaconate’s function in vivo, wild-type and ACOD1-/- mice were trained with β-glucan or PBS for 3 weeks before sacrifice. Plasma from β-glucan-trained wild-type mice exhibited greater thrombin generation compared to plasma from PBS-administered mice, but plasma from ACOD1-/- mice exhibited significantly reduced thrombin generation, even in mice previously trained with β-glucan. A β-glucan-induced increase in bone marrow myelopoiesis was observed in wild-type mice but not in ACOD1-/- mice. Remarkably, haematopoietic progenitor cells from β-glucan-trained mice possessed enhanced procoagulant activity compared to PBS-treated mice, but this effect was lost in cells from the ACOD1-/- mice.

Conclusion(s): Endogenous itaconate represents a tractable therapeutic target for attenuating thromboembolic risk in inflammatory diseases associated with maladaptive trained immunity.