PDF herunterladen
Thromb Haemost 2013; 110(06): 1267-1277
DOI: 10.1160/TH13-01-0017
Platelets and Blood Cells
Schattauer GmbH

CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice

Helga D. Manthey   *
1   Rudolf Center for Experimental Medicine, University of Würzburg, Wurzburg, Germany
,
Clément Cochain   *
2   Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
,
Stefanie Barnsteiner   *
1   Rudolf Center for Experimental Medicine, University of Würzburg, Wurzburg, Germany
,
Ela Karshovska
3   Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
,
Jaroslav Pelisek
2   Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
,
Miriam Koch
1   Rudolf Center for Experimental Medicine, University of Würzburg, Wurzburg, Germany
,
Sweena M. Chaudhari
1   Rudolf Center for Experimental Medicine, University of Würzburg, Wurzburg, Germany
2   Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
,
Martin Busch
1   Rudolf Center for Experimental Medicine, University of Würzburg, Wurzburg, Germany
,
Hans-Henning Eckstein
2   Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
4   DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
,
Christian Weber
3   Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
4   DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
,
Rory R. Koenen
3   Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
,
Alma Zernecke
2   Department of Vascular Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
4   DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
› Institutsangaben Financial support: This work was supported by the Deutsche Forschungsgemeinschaft (Hu1618/1–2 to R.R.K, and SFB688 TP A12, ZE 827/1–2 and ZE 827/4–1 to A.Z.), and ZonMW VIDI 016.126.358 to R.R.K.
Weitere Informationen

Publikationsverlauf

Received: 09. Januar 2013

Accepted after major revision: 19. August 2013

Publikationsdatum:
30. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

The chemokine receptor CCR6 is expressed by various cell subsets implicated in atherogenesis, such as monocytes, Th17 and regulatory T cells. In order to further define the role of CCR6 in atherosclerosis, CCR6-deficient (Ccr6 -/-) mice were crossed with low-density lipoprotein receptor-deficient (Ldlr -/-) mice to generate atherosclerosis-prone mice deficient in CCR6. Compared to Ldlr -/- controls, atherosclerotic burden in the aortic sinus and aorta were reduced in Ccr6 -/- Ldlr -/- mice fed a high fat diet, associated with a profound depression in lesional macrophage accumulation. Local and systemic distributions of T cells, including frequencies of Th1, Th17 and regulatory T cells were unaltered. In contrast, circulating counts of both Gr-1high and Gr1low monocytes were reduced in Ccr6 -/- Ldlr -/- mice. Moreover, CCR6 was revealed to promote monocyte adhesion to inflamed endothelium in vitro and leukocyte adhesion to carotid arteries in vivo. Finally, CCR6 selectively recruited monocytes but not T cells in an acute inflammatory air pouch model. We here show that CCR6 functions on multiple levels and regulates the mobilisation, adhesion and recruitment of monocytes/macrophages to the inflamed vessel, thereby promoting atherosclerosis, but is dispensable for hypercholesterolaemia-associated adaptive immune priming. Targeting CCR6 or its ligand CCL20 may therefore be a promising therapeutic strategy to alleviate atherosclerosis.

Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.

Keywords

Atherosclerosis - chemokines - CCR6 - monocyte - recruitment

* Equal contribution by these authors.


 

  • References

  • 1 Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nature reviews Immunology 2008; 8: 802-815.
    CrossrefPubMedSuche in Google Scholar
  • 2 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
    CrossrefPubMedSuche in Google Scholar
  • 3 Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009; 27: 669-692.
    CrossrefPubMedSuche in Google Scholar
  • 4 Tacke F, Alvarez D, Kaplan TJ. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117: 185-194.
    CrossrefPubMedSuche in Google Scholar
  • 5 Swirski FK, Libby P, Aikawa E. et al. Ly-6Chi monocytes dominate hypercholesterolaemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
    CrossrefPubMedSuche in Google Scholar
  • 6 Soehnlein O, Drechsler M, Doring Y. et al. Distinct functions of chemokine receptor axes in the atherogenic mobilisation and recruitment of classical monocytes. EMBO Mol Med 2013; 5: 471-481.
    CrossrefPubMedSuche in Google Scholar
  • 7 Combadiere C, Potteaux S, Rodero M. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolaemic mice. Circulation 2008; 117: 1649-1657.
    CrossrefPubMedSuche in Google Scholar
  • 8 Zernecke A, Weber C. Chemokines in the vascular inflammatory response of atherosclerosis. Cardiovasc Res 2010; 86: 192-201.
    CrossrefPubMedSuche in Google Scholar
  • 9 Ley K, Laudanna C, Cybulsky MI. et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7: 678-689.
    CrossrefPubMedSuche in Google Scholar
  • 10 Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 2009; 27: 165-197.
    CrossrefPubMedSuche in Google Scholar
  • 11 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
    CrossrefPubMedSuche in Google Scholar
  • 12 Taleb S, Tedgui A, Mallat Z. Adaptive T cell immune responses and atherogenesis. Curr Opin Pharmacol 2010; 10: 197-202.
    CrossrefPubMedSuche in Google Scholar
  • 13 Taleb S, Tedgui A, Mallat Z. Interleukin-17: friend or foe in atherosclerosis?. Current Opin Lipidol 2010; 21: 404-408.
    CrossrefPubMedSuche in Google Scholar
  • 14 Yilmaz A, Lipfert B, Cicha I. et al. Accumulation of immune cells and high expression of chemokines/chemokine receptors in the upstream shoulder of atherosclerotic carotid plaques. Exp Mol Pathol 2007; 82: 245-255.
    CrossrefPubMedSuche in Google Scholar
  • 15 Wan W, Lim JK, Lionakis MS. et al. Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice. Circ Res 2011; 109: 374-381.
    CrossrefPubMedSuche in Google Scholar
  • 16 Calvayrac O, Rodriguez-Calvo R, Alonso J. et al. CCL20 is increased in hypercholesterolaemic subjects and is upregulated by LDL in vascular smooth muscle cells: role of NF-kappaB. Arterioscler Thromb Vasc Biol 2011; 31: 2733-2741.
    CrossrefPubMedSuche in Google Scholar
  • 17 Korn T, Bettelli E, Oukka M. et al. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485-517.
    CrossrefPubMedSuche in Google Scholar
  • 18 Yamazaki T, Yang XO, Chung Y. et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 2008; 181: 8391-8401.
    CrossrefPubMedSuche in Google Scholar
  • 19 Robbins CS, Chudnovskiy A, Rauch PJ. et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation 2012; 125: 364-374.
    CrossrefPubMedSuche in Google Scholar
  • 20 Meissner A, Zilles O, Varona R. et al. CC chemokine ligand 20 partially controls adhesion of naive B cells to activated endothelial cells under shear stress. Blood 2003; 102: 2724-2727.
    CrossrefPubMedSuche in Google Scholar
  • 21 Wan W, Murphy PM. Regulation of atherogenesis by chemokine receptor CCR6. Trends Cardiovasc Med 2011; 21: 140-144.
    CrossrefPubMedSuche in Google Scholar
  • 22 Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 2006; 7: 311-317.
    CrossrefPubMedSuche in Google Scholar
  • 23 Swirski FK, Nahrendorf M, Etzrodt M. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 2009; 325: 612-616.
    CrossrefPubMedSuche in Google Scholar
  • 24 Landsman L, Bar-On L, Zernecke A. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 2009; 113: 963-972.
    CrossrefPubMedSuche in Google Scholar
  • 25 Wen H, Hogaboam CM, Lukacs NW. et al. The chemokine receptor CCR6 is an important component of the innate immune response. Eur J Immunol 2007; 37: 2487-2498.
    CrossrefPubMedSuche in Google Scholar
  • 26 Lortat-Jacob H. The molecular basis and functional implications of chemokine interactions with heparan sulphate. Curr Opin Struct Biol 2009; 19: 543-548.
    CrossrefPubMedSuche in Google Scholar
  • 27 Lortat-Jacob H, Grosdidier A, Imberty A. Structural diversity of heparan sulfate binding domains in chemokines. Proc Natl Acad Sci USA 2002; 99: 1229-1234.
    CrossrefPubMedSuche in Google Scholar
  • 28 Shantsila E, Devitt A, Lip GY. Circulating monocytes and atherogenesis: from animal experiments to human studies. Thromb Haemost 2010; 104: 191-193.
    Thieme ConnectPubMedSuche in Google Scholar
  • 29 Rogacev KS, Cremers B, Zawada AM. et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012; 60: 1512-1520.
    CrossrefPubMedSuche in Google Scholar
  • 30 Hristov M, Weber C. Differential role of monocyte subsets in atherosclerosis. Thromb Haemost 2011; 106: 757-762.
    Thieme ConnectPubMedSuche in Google Scholar
  • 31 Cros J, Cagnard N, Woollard K. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010; 33: 375-386.
    CrossrefPubMedSuche in Google Scholar