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Monocyte Subsets Differentially Employ CCR2, CCR5, and CX3CR1 to Accumulate Within Atherosclerotic Plaques

Overview

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2007 Jan 4

PMID 17200718

Citations 708

Authors

Authors

Frank Tacke

David Alvarez

Theodore J Kaplan

Claudia Jakubzick

Rainer Spanbroek

Jaime Llodra

Alexandre Garin

Jianhua Liu

Matthias Mack

Nico van Rooijen

Sergio A Lira

Andreas J Habenicht

Gwendalyn J Randolph

Affiliations

Affiliations

Soon will be listed here.

Abstract

Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE(-/-) mice and skewed toward an increased frequency of CCR2(+)Ly-6C(hi) monocytes in apoE(-/-) mice fed a high-fat diet. CCR2(+)Ly-6C(hi) monocytes efficiently accumulated in plaques, whereas CCR2(-)Ly-6C(lo) monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell-associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2(-) monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE(-/-) mice. By comparison, CCR2(+)Ly-6C(hi) monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2(+) monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.

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References

1.

Jung S, Aliberti J, Graemmel P, Sunshine M, Kreutzberg G, Sher A . Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000; 20(11):4106-14. PMC: 85780. DOI: 10.1128/MCB.20.11.4106-4114.2000. View

2.

Tacke F, Ginhoux F, Jakubzick C, van Rooijen N, Merad M, Randolph G . Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery. J Exp Med. 2006; 203(3):583-97. PMC: 2118235. DOI: 10.1084/jem.20052119. View

3.

Weber C, Belge K, von Hundelshausen P, Draude G, Steppich B, Mack M . Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol. 2000; 67(5):699-704. DOI: 10.1002/jlb.67.5.699. View

4.

Mack M, Cihak J, SIMONIS C, Luckow B, Proudfoot A, Plachy J . Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J Immunol. 2001; 166(7):4697-704. DOI: 10.4049/jimmunol.166.7.4697. View

5.

Cook D, Chen S, Sullivan L, Manfra D, Wiekowski M, Prosser D . Generation and analysis of mice lacking the chemokine fractalkine. Mol Cell Biol. 2001; 21(9):3159-65. PMC: 86945. DOI: 10.1128/MCB.21.9.3159-3165.2001. View

6.

Huo Y, Weber C, Forlow S, Sperandio M, Thatte J, Mack M . The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest. 2001; 108(9):1307-14. PMC: 209441. DOI: 10.1172/JCI12877. View

7.

Palframan R, Jung S, Cheng G, Weninger W, Luo Y, Dorf M . Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med. 2001; 194(9):1361-73. PMC: 2195988. DOI: 10.1084/jem.194.9.1361. View

8.

Randolph G, Sanchez-Schmitz G, Liebman R, Schakel K . The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J Exp Med. 2002; 196(4):517-27. PMC: 2196052. DOI: 10.1084/jem.20011608. View

9.

Jung S, Unutmaz D, Wong P, Sano G, de Los Santos K, Sparwasser T . In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity. 2002; 17(2):211-20. PMC: 3689299. DOI: 10.1016/s1074-7613(02)00365-5. View

10.

Wong B, Wong D, McManus B . Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol. 2002; 11(6):332-8. DOI: 10.1016/s1054-8807(02)00111-4. View

11.

Lesnik P, Haskell C, Charo I . Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003; 111(3):333-40. PMC: 151849. DOI: 10.1172/JCI15555. View

12.

Qu C, Edwards E, Tacke F, Angeli V, Llodra J, Sanchez-Schmitz G . Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J Exp Med. 2004; 200(10):1231-41. PMC: 2211916. DOI: 10.1084/jem.20032152. View

13.

Lindquist R, Shakhar G, Dudziak D, Wardemann H, Eisenreich T, Dustin M . Visualizing dendritic cell networks in vivo. Nat Immunol. 2004; 5(12):1243-50. DOI: 10.1038/ni1139. View

14.

Teupser D, Pavlides S, Tan M, Gutierrez-Ramos J, Kolbeck R, Breslow J . Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. Proc Natl Acad Sci U S A. 2004; 101(51):17795-800. PMC: 539720. DOI: 10.1073/pnas.0408096101. View

15.

Duffield J, Forbes S, Constandinou C, Clay S, Partolina M, Vuthoori S . Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005; 115(1):56-65. PMC: 539199. DOI: 10.1172/JCI22675. View

16.

Hendrik Niess J, Brand S, Xiubin Gu , Landsman L, Jung S, McCormick B . CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005; 307(5707):254-8. DOI: 10.1126/science.1102901. View

17.

Smalley D, Ley K . L-selectin: mechanisms and physiological significance of ectodomain cleavage. J Cell Mol Med. 2005; 9(2):255-66. PMC: 6740228. DOI: 10.1111/j.1582-4934.2005.tb00354.x. View

18.

Yates R, Russell D . Phagosome maturation proceeds independently of stimulation of toll-like receptors 2 and 4. Immunity. 2005; 23(4):409-17. DOI: 10.1016/j.immuni.2005.09.007. View

19.

Ginhoux F, Tacke F, Angeli V, Bogunovic M, Loubeau M, Dai X . Langerhans cells arise from monocytes in vivo. Nat Immunol. 2006; 7(3):265-73. PMC: 4727824. DOI: 10.1038/ni1307. View

20.

Combadiere C, Potteaux S, Gao J, Esposito B, Casanova S, Lee E . Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation. 2003; 107(7):1009-16. DOI: 10.1161/01.cir.0000057548.68243.42. View