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

Andrew Scott Kimball; Andrea Tara Obi; Catherine E. Luke; Abigail R. Dowling; Qing Cai; Reheman Adili; Hannah Jankowski; Matthew Schaller; Michael Holinstadt; Farouc A. Jaffer; Steven L. Kunkel; Katherine A. Gallagher; Peter K. Henke

doi:10.1055/s-0039-3400959

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2020; 120(02): 289-299
DOI: 10.1055/s-0039-3400959

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

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

Andrew Scott Kimball^*

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Andrea Tara Obi ^*

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Catherine E. Luke

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Abigail R. Dowling

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Qing Cai

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Reheman Adili

²Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States

,

Hannah Jankowski

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Matthew Schaller

³Division of Pulmonary Critical Care Medicine, University of Florida, Gainesville, Florida, United States

,

Michael Holinstadt

²Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States

,

Farouc A. Jaffer

⁴Department of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, United States

,

Steven L. Kunkel

⁵Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States

,

Katherine A. Gallagher

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

,

Peter K. Henke

¹Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States

› Institutsangaben

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⁺Ly6C^Hi) or proreparative (CD11b⁺Ly6C^Lo) 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⁺Ly6C^Lo Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11b⁺Ly6C^Hi Mo/MΦ recruitment, suggesting a protective effect of CD11b⁺Ly6C^Lo 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⁺Ly6C^Lo Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11b⁺Ly6C^Lo 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.

Keywords

venous thromboembolism - thrombosis - macrophages - monocytes - inflammation

Volltext

Referenzen

References
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