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Ly6C Lo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis

Authors
  • Kimball, Andrew Scott1
  • Obi, Andrea Tara1
  • Luke, Catherine E.1
  • Dowling, Abigail R.1
  • Cai, Qing1
  • Adili, Reheman2
  • Jankowski, Hannah1
  • Schaller, Matthew3
  • Holinstadt, Michael2
  • Jaffer, Farouc A.4
  • Kunkel, Steven L.5
  • Gallagher, Katherine A.1
  • Henke, Peter K.1
  • 1 Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
  • 2 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States
  • 3 Division of Pulmonary Critical Care Medicine, University of Florida, Gainesville, Florida, United States
  • 4 Department of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, United States
  • 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States
Type
Published Article
Journal
Thrombosis and Haemostasis
Publisher
Georg Thieme Verlag KG
Publication Date
Dec 30, 2019
Volume
120
Issue
2
Pages
289–299
Identifiers
DOI: 10.1055/s-0039-3400959
PMID: 31887775
PMCID: PMC7365023
Source
PubMed Central
Keywords
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.

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