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The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium - PubMed

The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium

Y Huo et al. J Clin Invest. 2001 Nov.

Abstract

In a reconstituted flow chamber system, preincubation with chemokines can trigger the arrest of rolling monocytes, suggesting that this interaction could help recruit these cells to early atherosclerotic lesions. To date, however, the contribution of endothelium-derived chemokines found in these lesion to monocyte arrests has not been investigated. The endothelium of lesion-prone carotid arteries from apolipoprotein E-deficient (ApoE(-/-)) mice, but not control mice, presents the chemokines KC (mouse GRO-alpha) and JE (mouse monocyte chemoattractant protein-1 [MCP-1]). Arrest of a monocytic cell line or mouse blood monocytes perfused through carotid arteries of ApoE(-/-) mice was reduced by treating with either pertussis toxin, an antagonist of CXCR2, or an antibody to KC, but this process was insensitive to agents that blocked CCR-2 or JE. Conversely, monocyte accumulation more than doubled upon pre-perfusion of the carotid artery with KC but not with mouse MCP-1. Blockade of alpha(4)beta(1) integrin (VLA-4) or vascular cell adhesion molecule-1, but not CD18 or intercellular adhesion molecule-1, almost completely inhibited the arrest of monocytes. We conclude that when presented by early atherosclerotic lesions, KC but not murine MCP-1 triggers VLA-4-dependent monocyte recruitment.

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Figures

Figure 1
Figure 1

Monocyte activation through Giα-coupled receptors promotes monocyte accumulation on native early atherosclerotic endothelium. (a) MM6 cell arrest in perfused apoE–/– mouse carotid arteries is significantly inhibited by pertussis toxin (PTX; *P < 0.01, mean ± SEM of six independent experiments per group), but not by mutant PTX (mPTX). (b) PTX inhibits mouse blood monocyte arrest on native early atherosclerotic endothelium (*P < 0.01, mean ± SEM of three independent experiments per group).

Figure 2
Figure 2

Chemokines expressed on early atherosclerotic endothelium of mouse carotid arteries. KC is strongly expressed on the endothelium and throughout the media of carotid arteries of apoE–/– mice fed a Western diet for 5 weeks (b). JE (mouse MCP-1) is also highly expressed (c). Goat IgG produces no staining of the same vessel. (a).

Figure 3
Figure 3

Effects of blocking chemokines and chemokine receptors on MM6 cell arrest on early atherosclerotic endothelium. (a) Blockade of CXCR2 by 8-73GRO, but neither blockade of CCR2 by 9-76MCP-1 nor neutralization of JE by a blocking antibody, leads to a decrease in MM6 cell arrest (*P < 0.01, mean ± SEM, n = 6). (b) The 9-76MCP-1 (5 μg/ml) and JE blocking antibody (10 μg/ml) each completely inhibit MM6 cell transmigration response to JE (three experiments). (c) Blockade of CXCR2 by 8-73GRO but not CCR2 by 9-76MCP-1 or of JE by a blocking antibody leads to decreased mouse monocyte arrest (*P < 0.01, mean ± SEM, n = 5).

Figure 4
Figure 4

Role of KC on MM6 cell arrest on early atherosclerotic endothelium. MM6 cell accumulation at 5 minutes, normalized to control. Blocking CXCR2 with 8-73GRO, KC with an antibody, or both reduces cell accumulation (*P < 0.01, mean ± SEM, n = 6). An MIP-2 antibody has no effect, either alone or in combination with KC antibody. Blocking CXCR2 with 8-73GRO does not further reduce accumulation of PTX-treated cells.

Figure 5
Figure 5

Additional loading of KC increases monocyte arrest on early atherosclerotic endothelium. (a) KC, but not JE, perfusion increases MM6 cell arrest on early atherosclerotic endothelium (*P < 0.01, mean ± SEM, n = 3). Increased accumulation is blocked by PTX. (b) KC, but not JE, perfusion increases mouse monocyte arrest on early atherosclerotic endothelium (*P < 0.01, mean ± SEM, n = 3).

Figure 6
Figure 6

VLA-4 is responsible for chemokine-mediated MM6 arrest on early atherosclerotic endothelium. (a) Blocking VLA-4 (mAb HP1/2), but not CD18 (mAb IB4), blocks MM6 cell arrest on early atherosclerotic endothelium (*P < 0.01, mean ± SEM, n = 3). (b) Increased MM6 cell arrest after KC perfusion is also inhibited by mAb HP1/2, but not IB4 (*P < 0.01, mean ± SEM, n = 3). (c) Blocking VLA-4 (mAb PS/2) or VCAM-1 (mAb MK2/7), but not CD18 (mAb GAME-46) or ICAM-1 (mAb YN1), inhibits mouse blood monocyte arrest on early atherosclerotic endothelium (*P < 0.01, mean ± SEM, n = 3).

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