Abstract Number: OC 14.4
Meeting: ISTH 2020 Congress
Background: Macrophage ‘training’ or ‘memory’ describes the recently discovered phenomenon in which innate immune cells undergo extensive epigenetic and metabolic alterations in response to a specific pathogen exposure that increases their responsiveness to a subsequent, non-specific pathogenic stimuli. Dysregulated innate immune cell ‘training’ has been implicated in the pathophysiology of various inflammatory diseases, however, its impact on macrophage hemostatic activity is currently unknown.
Aims: To characterize whether induction of innate immune memory in macrophages modulates their procoagulant phenotype.
Methods: Murine bone marrow-derived macrophages were exposed to heat-killed Candida albicans or β-glucan to induce training, washed, then left for 7 days before lipopolysaccharide (LPS) re-stimulation. Macrophage gene expression and function were analyzed by ELISA, RT-PCR, calibrated automated thrombinography and plasmin generation assays.
Results: Gene expression analysis of trained macrophages identified significant alterations in procoagulant and antifibrinolytic gene expression. In particular, tissue factor (TF) expression on trained macrophages was enhanced 15-fold compared to naïve macrophages and 4-fold enhanced compared to untrained macrophages stimulated with LPS. TF-dependent thrombin generation in the presence of trained macrophages or trained macrophage supernatant was associated with significantly shortened lag-time compared to when LPS-stimulated untrained macrophages were present. Pre-treatment with methyltransferase and acetyltransferase inhibitors to erase epigenetic marks associated with innate immune memory diminished trained macrophage TF expression and extended thrombin generation lag-time to that of untrained macrophages. Moreover, trained macrophages exhibited 100-fold enhanced plasminogen activator inhibitor-1 (PAI-1) expression and demonstrated increased capacity to restrict plasmin generation.
Conclusions: These novel data demonstrate that induction of innate immune memory in macrophages accelerates their procoagulant activity by enhanced induction of TF expression and increased release of TF-containing extracellular vesicles. Moreover, trained macrophages also exhibit markedly increased antifibrinolytic activity. Induction of immune memory in innate immune cells therefore lowers the threshold for expression of their pro-inflammatory, procoagulant and antifibrinolytic activities to collectively boost their haemostatic potential.
To cite this abstract in AMA style:McCluskey S, Rehill A, Preston R. Induction of Innate Immune Memory in Macrophages Profoundly Enhances their Procoagulant and Antifibrinolytic Activity [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/induction-of-innate-immune-memory-in-macrophages-profoundly-enhances-their-procoagulant-and-antifibrinolytic-activity/. Accessed January 26, 2022.
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