Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability
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Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability. / Rehill, Aisling M; Leon, Gemma; McCluskey, Sean; Schoen, Ingmar; Hernandez-Santana, Yasmina; Annett, Stephanie; Klavina, Paula; Robson, Tracy; Curtis, Annie M; Renné, Thomas; Hussey, Seamus; O'Donnell, James S; Walsh, Patrick T; Preston, Roger J S.
In: J THROMB HAEMOST, Vol. 22, No. 2, 02.2024, p. 394-409.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability
AU - Rehill, Aisling M
AU - Leon, Gemma
AU - McCluskey, Sean
AU - Schoen, Ingmar
AU - Hernandez-Santana, Yasmina
AU - Annett, Stephanie
AU - Klavina, Paula
AU - Robson, Tracy
AU - Curtis, Annie M
AU - Renné, Thomas
AU - Hussey, Seamus
AU - O'Donnell, James S
AU - Walsh, Patrick T
AU - Preston, Roger J S
N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2024/2
Y1 - 2024/2
N2 - BACKGROUND: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.OBJECTIVES: We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.METHODS: We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease.RESULTS: Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity through reduced plasminogen activator inhibitor 1 activity. Macrophage polarization or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and activated protein C generation compared with macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice.CONCLUSION: Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thromboinflammatory disease.
AB - BACKGROUND: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.OBJECTIVES: We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.METHODS: We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease.RESULTS: Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity through reduced plasminogen activator inhibitor 1 activity. Macrophage polarization or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and activated protein C generation compared with macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice.CONCLUSION: Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thromboinflammatory disease.
U2 - 10.1016/j.jtha.2023.10.006
DO - 10.1016/j.jtha.2023.10.006
M3 - SCORING: Journal article
C2 - 37865288
VL - 22
SP - 394
EP - 409
JO - J THROMB HAEMOST
JF - J THROMB HAEMOST
SN - 1538-7933
IS - 2
ER -