LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression
LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression
复制标题
DOI：
10.1172/jci38911
复制
发表时间：
2010-12-01
影响因子：
15.9
通讯作者：
Fisher, Edward A.
中科院分区：
文献类型：
--
作者：
Feig, Jonathan E.;Pineda-Torra, Ines;Fisher, Edward A.
我们之前的研究表明，小鼠动脉粥样硬化的消退涉及斑块中单核细胞来源（CD68(+)）细胞的迁移，并依赖于趋化因子受体CCR7。与此同时，斑块CD68（+）细胞中编码LXR α的基因mRNA水平升高，提示LXR和CCR7之间存在功能关系。为了扩展这些结果，用LXR激动剂治疗CCR7充足或缺乏的动脉粥样硬化Apoe（-/-）小鼠，导致斑块CD68（+）细胞的CCR7依赖性减少。为了测试LXR对ccr7依赖性回归的要求，我们将动脉粥样硬化Apoe（-/-）小鼠的主动脉弓移植到WT受体中，或者从LXR α或LXR β缺乏的Apoe（-/-）小鼠移植到WT受体中。LXR α -和LXR β -缺陷Apoe（-/-）小鼠的斑块均表现出退化受损。此外，CD68（+）细胞显示出迁移和CCR7表达减少。使用未成熟的DC细胞系，我们发现LXR激动剂治疗增加了Ccr7 mRNA水平。当sirna降低LXR α和LXR β水平时，这种增加被减弱。此外，LXR激动剂治疗原发性人未成熟dc可导致CCR7在功能上显著上调。我们得出结论，在小鼠动脉粥样硬化消退过程中，LXR对斑块CD68（+）细胞CCR7的表达和单核细胞衍生细胞的分泌有最大的影响。
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 LXR alpha 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 LXR alpha or LXR beta, into WT recipients. Plaques from both LXR alpha- and LXR beta-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 LXR alpha and LXR beta 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.