LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression
Jonathan E. Feig, Ines Pineda-Torra, Marie Sanson, Michelle N. Bradley, Yuliya Vengrenyuk, Dusan Bogunovic, Emmanuel L. Gautier, Daniel Rubinstein, Cynthia Hong, Jianhua Liu, Chaowei Wu, Nico van Rooijen, Nina Bhardwaj, Michael J. Garabedian, Peter Tontonoz, Edward A. Fisher
Jonathan E. Feig, Ines Pineda-Torra, Marie Sanson, Michelle N. Bradley, Yuliya Vengrenyuk, Dusan Bogunovic, Emmanuel L. Gautier, Daniel Rubinstein, Cynthia Hong, Jianhua Liu, Chaowei Wu, Nico van Rooijen, Nina Bhardwaj, Michael J. Garabedian, Peter Tontonoz, Edward A. Fisher
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Research Article Cardiology

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

Abstract

We have previously shown that mouse atherosclerosis regression involves monocyte-derived (CD68+) cell emigration from plaques and is dependent on the chemokine receptor CCR7. Concurrent with regression, mRNA levels of the gene encoding LXRα are increased in plaque CD68+ cells, suggestive of a functional relationship between LXR and CCR7. To extend these results, atherosclerotic Apoe–/– mice sufficient or deficient in CCR7 were treated with an LXR agonist, resulting in a CCR7-dependent decrease in plaque CD68+ cells. To test the requirement for LXR for CCR7-dependent regression, we transplanted aortic arches from atherosclerotic Apoe–/– mice, or from Apoe–/– mice with BM deficiency of LXRα or LXRβ, into WT recipients. Plaques from both LXRα- and LXRβ-deficient Apoe–/– mice exhibited impaired regression. In addition, the CD68+ cells displayed reduced emigration and CCR7 expression. Using an immature DC line, we found that LXR agonist treatment increased Ccr7 mRNA levels. This increase was blunted when LXRα and LXRβ levels were reduced by siRNAs. Moreover, LXR agonist treatment of primary human immature DCs resulted in functionally significant upregulation of CCR7. We conclude that LXR is required for maximal effects on plaque CD68+ cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice.

Authors

Jonathan E. Feig, Ines Pineda-Torra, Marie Sanson, Michelle N. Bradley, Yuliya Vengrenyuk, Dusan Bogunovic, Emmanuel L. Gautier, Daniel Rubinstein, Cynthia Hong, Jianhua Liu, Chaowei Wu, Nico van Rooijen, Nina Bhardwaj, Michael J. Garabedian, Peter Tontonoz, Edward A. Fisher

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Figure 1

Activation of LXR increases CCR7 expression in atherosclerotic lesions and promotes plaque regression.

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Activation of LXR increases CCR7 expression in atherosclerotic lesions a...
Apoe–/– mice (n = 30) were placed on Western diet for 16 weeks, after which they were injected intravenously with either LXR agonist or saline daily for 2 weeks. At the end of the treatment period, plasma lipids were measured (A), and lesional CD68+ cell content was determined (B). Ccr7–/–Apoe–/– mice (n = 7) were treated as above with LXR agonist, and the CD68+ content of the atherosclerotic lesions was determined (C). In addition, CD68+ cells from Apoe–/– mice were laser captured and the isolated RNA used for qRT-PCR measurements of the indicated mRNAs (normalized to Ppia, which encodes cyclophilin A) (D). The increase in Ccr7 mRNA in samples from agonist-treated mice was confirmed at the protein level by immunostaining (E and F; original magnification, ×400). The striped green background signal is due to autofluorescence from the internal elastic lamina from the medial layer of the artery. *P < 0.05 versus saline.