PDF herunterladen
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
,
Andrea Tara Obi    *
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
› Institutsangaben Funding This work was supported by the NIH: R01HL132988–03; T32HL076123–14 and Jobst Foundation grant from the American Venous Forum.
Weitere Informationen

Publikationsverlauf

10. Oktober 2019

27. Oktober 2019

Publikationsdatum:
30. Dezember 2019 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Leserbrief zu:

Myeloid Cells to the Rescue: Improving Thrombus ResolutionThromb Haemost 2020; 120(02): 197-198
DOI: 10.1055/s-0039-1701044

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.

Keywords

venous thromboembolism - thrombosis - macrophages - monocytes - inflammation

* Shared authorship.


Supplementary Material

 

  • References

  • 1 Anderson Jr FA, Wheeler HB, Goldberg RJ. , et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (05) 933-938
    CrossrefPubMedGoogle Scholar
  • 2 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedGoogle Scholar
  • 3 Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3 (08) 1843-1853
    CrossrefPubMedGoogle Scholar
  • 4 Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016; 388 (10063): 3060-3073
    CrossrefPubMedGoogle Scholar
  • 5 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (03) 387-391
    CrossrefPubMedGoogle Scholar
  • 6 Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016; 128 (06) 753-762
    PubMedGoogle Scholar
  • 7 Saha P, Humphries J, Modarai B. , et al. Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 2011; 31 (03) 506-512
    CrossrefPubMedGoogle Scholar
  • 8 Budnik I, Brill A. Immune factors in deep vein thrombosis initiation. Trends Immunol 2018; 39 (08) 610-623
    CrossrefPubMedGoogle Scholar
  • 9 Henke PK, Varga A, De S. , et al. Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity in a mouse model. Arterioscler Thromb Vasc Biol 2004; 24 (06) 1130-1137
    CrossrefPubMedGoogle Scholar
  • 10 Laser A, Elfline M, Luke C. , et al. Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling. Arterioscler Thromb Vasc Biol 2014; 34 (02) 377-385
    CrossrefPubMedGoogle Scholar
  • 11 Henke PK, Pearce CG, Moaveni DM. , et al. Targeted deletion of CCR2 impairs deep vein thrombosis resolution in a mouse model. J Immunol 2006; 177 (05) 3388-3397
    CrossrefPubMedGoogle Scholar
  • 12 Henke PK, Mitsuya M, Luke CE. , et al. Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution. Arterioscler Thromb Vasc Biol 2011; 31 (01) 43-49
    CrossrefPubMedGoogle Scholar
  • 13 Kessinger CW, Kim JW, Henke PK. , et al. Statins improve the resolution of established murine venous thrombosis: reductions in thrombus burden and vein wall scarring. PLoS One 2015; 10 (02) e0116621
    CrossrefPubMedGoogle Scholar
  • 14 Nathan C, Ding A. Nonresolving inflammation. Cell 2010; 140 (06) 871-882
    CrossrefPubMedGoogle Scholar
  • 15 Ali T, Humphries J, Burnand K. , et al. Monocyte recruitment in venous thrombus resolution. J Vasc Surg 2006; 43 (03) 601-608
    CrossrefPubMedGoogle Scholar
  • 16 Gallagher KA, Obi AT, Elfline MA. , et al. Alterations in macrophage phenotypes in experimental venous thrombosis. J Vasc Surg Venous Lymphat Disord 2016; 4 (04) 463-471
    PubMedGoogle Scholar
  • 17 Fuchs TA, Brill A, Duerschmied D. , et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
    CrossrefPubMedGoogle Scholar
  • 18 Stark K, Philippi V, Stockhausen S. , et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016; 128 (20) 2435-2449
    CrossrefPubMedGoogle Scholar
  • 19 Chang CF, Goods BA, Askenase MH. , et al. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest 2017
    PubMedGoogle Scholar
  • 20 Singh I, Burnand KG, Collins M. , et al. Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation 2003; 107 (06) 869-875
    CrossrefPubMedGoogle Scholar
  • 21 Henke PK, Varma MR, Moaveni DK. , et al. Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis. Thromb Haemost 2007; 98 (05) 1045-1055
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 22 Murray PJ, Allen JE, Biswas SK. , et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41 (01) 14-20
    CrossrefPubMedGoogle Scholar
  • 23 Jablonski KA, Amici SA, Webb LM. , et al. Novel markers to delineate murine M1 and M2 macrophages. PLoS One 2015; 10 (12) e0145342
    CrossrefPubMedGoogle Scholar
  • 24 Arnold L, Henry A, Poron F. , et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 2007; 204 (05) 1057-1069
    CrossrefPubMedGoogle Scholar
  • 25 Kimball A, Schaller M, Joshi A. , et al. Ly6CHi blood monocyte/macrophage drive chronic inflammation and impair wound healing in diabetes mellitus. Arterioscler Thromb Vasc Biol 2018; 38 (05) 1102-1114
    CrossrefPubMedGoogle Scholar
  • 26 Diaz JA, Obi AT, Myers Jr DD. , et al. Critical review of mouse models of venous thrombosis. Arterioscler Thromb Vasc Biol 2012; 32 (03) 556-562
    CrossrefPubMedGoogle Scholar
  • 27 Stoneman V, Braganza D, Figg N. , et al. Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques. Circ Res 2007; 100 (06) 884-893
    CrossrefPubMedGoogle Scholar
  • 28 Diaz JA, Wrobleski SK, Alvarado CM. , et al. P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor. Arterioscler Thromb Vasc Biol 2015; 35 (04) 829-837
    CrossrefPubMedGoogle Scholar
  • 29 Culmer DL, Dunbar ML, Hawley AE. , et al. E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model. Thromb Haemost 2017; 117 (06) 1171-1181
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 30 Dewyer NA, El-Sayed OM, Luke CE. , et al. Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury. Thromb Haemost 2015; 114 (05) 1028-1037
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 31 Gallagher KA, Joshi A, Carson WF. , et al. Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes 2015; 64 (04) 1420-1430
    CrossrefPubMedGoogle Scholar
  • 32 Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009; 27: 669-692
    CrossrefPubMedGoogle Scholar
  • 33 Nahrendorf M, Swirski FK, Aikawa E. , et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007; 204 (12) 3037-3047
    CrossrefPubMedGoogle Scholar
  • 34 Zigmond E, Varol C, Farache J. , et al. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 2012; 37 (06) 1076-1090
    CrossrefPubMedGoogle Scholar
  • 35 Schönfelder T, Brandt M, Kossmann S. , et al. Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis. Sci Rep 2018; 8 (01) 3013
    CrossrefPubMedGoogle Scholar
  • 36 Cailhier JF, Partolina M, Vuthoori S. , et al. Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation. J Immunol 2005; 174 (04) 2336-2342
    CrossrefPubMedGoogle Scholar
  • 37 von Brühl ML, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 38 Deroo S, Deatrick KB, Henke PK. The vessel wall: a forgotten player in post thrombotic syndrome. Thromb Haemost 2010; 104 (04) 681-692
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 39 Kimball AS, Obi AT, Diaz JA, Henke PK. The emerging role of NETs in venous thrombosis and immunothrombosis. Front Immunol 2016; 7: 236
    CrossrefPubMedGoogle Scholar
  • 40 Martinod K, Demers M, Fuchs TA. , et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 2013; 110 (21) 8674-8679
    CrossrefPubMedGoogle Scholar
  • 41 Ponomaryov T, Payne H, Fabritz L, Wagner DD, Brill A. Mast cells granular contents are crucial for deep vein thrombosis in mice. Circ Res 2017; 121 (08) 941-950
    CrossrefPubMedGoogle Scholar
  • 42 Henke PK, Varma MR, Deatrick KB. , et al. Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization. Thromb Haemost 2006; 95 (02) 272-281
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 43 Dal-Secco D, Wang J, Zeng Z. , et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J Exp Med 2015; 212 (04) 447-456
    CrossrefPubMedGoogle Scholar
  • 44 Perego C, Fumagalli S, Zanier ER. , et al. Macrophages are essential for maintaining a M2 protective response early after ischemic brain injury. Neurobiol Dis 2016; 96: 284-293
    CrossrefPubMedGoogle Scholar
  • 45 Rahman K, Vengrenyuk Y, Ramsey SA. , et al. Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest 2017; 127 (08) 2904-2915
    CrossrefPubMedGoogle Scholar
  • 46 Crane MJ, Daley JM, van Houtte O, Brancato SK, Henry Jr WL, Albina JE. The monocyte to macrophage transition in the murine sterile wound. PLoS One 2014; 9 (01) e86660
    CrossrefPubMedGoogle Scholar
  • 47 Motley MP, Madsen DH, Jürgensen HJ. , et al. A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood 2016; 127 (09) 1085-1096
    CrossrefPubMedGoogle Scholar
  • 48 Nosaka M, Ishida Y, Kimura A. , et al. Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice. J Clin Invest 2011; 121 (07) 2911-2920
    CrossrefPubMedGoogle Scholar