Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques - PubMed (original) (raw)

Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques

Jaime Llodrá et al. Proc Natl Acad Sci U S A. 2004.

Abstract

Some monocytes normally take up residence in tissues as sessile macrophages, but others differentiate into migratory cells resembling dendritic cells that emigrate to lymph nodes. In an in vitro model of a vessel wall, lipid mediators lysophosphatidic acid and platelet-activating factor, whose signals are implicated in promoting atherosclerosis, blocked conversion of monocytes into migratory cells and favored their retention in the subendothelium. In vivo studies revealed trafficking of monocyte-derived cells from atherosclerotic plaques during lesion regression, but little emigration was detected from progressive plaques. Thus, progression of atherosclerotic plaques may result not only from robust monocyte recruitment into arterial walls but also from reduced emigration of these cells from lesions.

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Figures

Fig. 1.

Fig. 1.

Effect of PAF and LPA signals on the migratory fate of monocyte-derived cells in a model of a vessel wall. Carbamyl PAF (filled symbols) or 18:1 LPA (open symbols) was added to the culture medium at the concentrations shown. Reverse transmigration (a) and neutral lipid uptake (b) were quantified. (c) Arrows indicate a monocyte just beneath the endothelium that accumulated neutral lipid heavily, as assessed by staining with oil red O (ORO). Arrowhead shows a leukocyte that did not accumulate lipid. Shown is a representative experiment of three conducted, all with similar results.

Fig. 2.

Fig. 2.

Assessment of methods and kinetics to study migration from lesions in vivo. (a) ApoE–/– male and female mice on a C57BL/6 Ly5.1 (CD45.1) congenic background were fed a Western-type diet from 4 to 19 weeks of age. Aortic arches from these donor mice were surgically implanted on the abdominal aorta of recipient mice (17). Each surgery included matched representatives of both genotypes, apoE+/+ and apoE–/–, for comparison between genotypes in side-by-side processing. Lesion area was quantified over a 2-week time course in an experimental design to compare outcomes in lesion size between apoE–/– and apoE+/+ recipients (five animals per time point) and to delineate the kinetics of regression in apoE+/+ recipients. * denotes significant change in lesion area from time 0, P < 0.02. Lesions examined at time 0 were stained with CD45.1 (b, red staining), CD68 (b, green staining that is in addition to autofluorescent green elastic lamina), and CD11c (c, red). Isotypematched control mAb did not stain the lesions (d). (e and f) Monocyte-derived cells from CD45.1 donor lesions (red staining, Left) or CD45.2 circulating monocytes of the recipient that were recruited to the lesion after surgical transfer (red staining, Right) were respectively identified in plaques 3 days after they were transferred to apoE+/+ or apoE–/– recipients. Counterstaining was with anti-CD68 mAb (green) and 4′,6-diamidino-2-phenylindole (blue). Green fluorescence was not recorded in c and d. lu denotes lumen of aorta.

Fig. 3.

Fig. 3.

Tracing emigration from lesions to lymph nodes. (a) Flow cytometric evaluation was carried out on apoE–/– and apoE+/+ recipients 3 days after transplant. CD45.2 nontranplanted mouse lymph nodes were routinely stained with biotinylated anti-CD45.1 mAb and streptavidin-allophycocyanin to determine the extent of mAb cross-reactivity. This measure was used to delineate the position of the negative control line in each plot as shown. Staining of CD45.1+ control lymph nodes (LN) with anti-CD45.1 mAb established that the positively stained cells were uniformly detectable above the cross-reactive threshold (lower left flow plot). Staining was routinely conducted in single suspensions of iliac lymph nodes that drain the transferred aortic segments, the brachial lymph nodes as a representative distant nondraining lymph nodes, and the hepatic lymph node. Representative plots are shown, and each depict flow cytometric evaluation of the entire lymph node population. (b) Plot charts the total number of CD45.1+ cells observed in the iliac lymph nodes of individuals (each symbol, one individual) 3 days after aortic transfer into apoE+/+ (WT) or apoE–/– (KO) recipients. Differences in the number of migrated cells are statistically significant, P <0.03. (c) Evaluation of CD115 staining is shown in the iliac lymph nodes of a representative apoE+/+ recipient (bold line in Total LN histogram) compared with iliac lymph node of nontransplanted mouse (filled histogram). CD115 and CD11c staining in gated CD45.1 cells (lower histogram pair) is shown. Negative staining is observed in peaks that fall between 100 and 101 log.

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