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Ly6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis.

Authors
  • Kimball, Andrew Scott1
  • Obi, Andrea Tara1
  • Luke, Catherine E1
  • Dowling, Abigail R1
  • Cai, Qing1
  • Adili, Reheman2
  • Jankowski, Hannah1
  • Schaller, Matthew3
  • Holinstadt, Michael2
  • Jaffer, Farouc A4
  • Kunkel, Steven L5
  • Gallagher, Katherine A1
  • Henke, Peter K1
  • 1 Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States. , (United States)
  • 2 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States. , (United States)
  • 3 Division of Pulmonary Critical Care Medicine, University of Florida, Gainesville, Florida, United States. , (United States)
  • 4 Department of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, United States. , (United States)
  • 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States. , (United States)
Type
Published Article
Journal
Thrombosis and Haemostasis
Publisher
Georg Thieme Verlag KG
Publication Date
Feb 01, 2020
Volume
120
Issue
2
Pages
289–299
Identifiers
DOI: 10.1055/s-0039-3400959
PMID: 31887775
Source
Medline
Language
English
License
Unknown

Abstract

Venous thrombosis (VT) resolution is a complex process, resembling sterile wound healing. Infiltrating blood-derived monocyte/macrophages (Mo/MΦs) are essential for the regulation of inflammation in tissue repair. These cells differentiate into inflammatory (CD11b+Ly6CHi) or proreparative (CD11b+Ly6CLo) subtypes. Previous studies have shown that infiltrating Mo/MΦs are important for VT resolution, but the precise roles of different Mo/MΦs subsets are not well understood. Utilizing murine models of stasis and stenosis inferior vena cava thrombosis in concert with a Mo/MΦ depletion model (CD11b-diphtheria toxin receptor [DTR]-expressing mice), we examined the effect of Mo/MΦ depletion on thrombogenesis and VT resolution. In the setting of an 80 to 90% reduction in circulating CD11b+Mo/MΦs, we demonstrated that Mo/MΦs are not essential for thrombogenesis, with no difference in thrombus size, neutrophil recruitment, or neutrophil extracellular traps found. Conversely, CD11b+Mo/MΦ are essential for VT resolution. Diphtheria toxoid (DTx)-mediated depletion after thrombus creation depleted primarily CD11b+Ly6CLo Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11b+Ly6CHi Mo/MΦ recruitment, suggesting a protective effect of CD11b+Ly6CLo Mo/MΦs in VT resolution. Confirmatory Mo/MΦ depletion with clodronate lysosomes showed a similar phenotype, with failure to resolve VT. Adoptive transfer of CD11b+Ly6CLo Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11b+Ly6CLo Mo/MΦs are essential for normal VT resolution, consistent with the known proreparative function of this subset, and that further study of Mo/MΦ subsets may identify targets for immunomodulation to accelerate and improve thrombosis resolution. Georg Thieme Verlag KG Stuttgart · New York.

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