Thromb Haemost 2020; 120(02): 289-299
DOI: 10.1055/s-0039-3400959
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

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

Andrew Scott Kimball*
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
Catherine E. Luke
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
Abigail R. Dowling
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
Qing Cai
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
Reheman Adili
2  Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States
,
Hannah Jankowski
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
Matthew Schaller
3  Division of Pulmonary Critical Care Medicine, University of Florida, Gainesville, Florida, United States
,
Michael Holinstadt
2  Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States
,
Farouc A. Jaffer
4  Department of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, United States
,
Steven L. Kunkel
5  Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States
,
Katherine A. Gallagher
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
,
Peter K. Henke
1  Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States
› Author Affiliations
Funding This work was supported by the NIH: R01HL132988–03; T32HL076123–14 and Jobst Foundation grant from the American Venous Forum.
Further Information

Publication History

10 October 2019

27 October 2019

Publication Date:
30 December 2019 (online)

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.

* Shared authorship.


Supplementary Material