Open AccessLy6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis
Author(s) -
Andrew Kimball,
Andrea Obi,
Catherine E. Luke,
Abigail Dowling,
Qing Cai,
Reheman Adili,
Hannah Jankowski,
Matthew Schaller,
Michael Holinstadt,
Farouc A. Jaffer,
Steven L. Kunkel,
Katherine Gallagher,
Peter K. Henke
Publication year - 2019
Publication title -
thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.97
H-Index - 188
eISSN - 2567-689X
pISSN - 0340-6245
DOI - 10.1055/s-0039-3400959
Subject(s) - thrombus , integrin alpha m , neutrophil extracellular traps , thrombosis , medicine , monocyte , inflammation , immunology , pathology , receptor
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.