Disrupting LXRa phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation
Disrupting LXRa phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation
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DOI：
10.1073/pnas.1721245115
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发表时间：
2018-07-10
影响因子：
11.1
通讯作者：
Pineda-Torra, I.
中科院分区：
文献类型：
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作者：
Gage, M. C.;Becares, N.;Pineda-Torra, I.
巨噬细胞是动脉粥样硬化病变发生和发展的关键免疫细胞。然而，决定病变如何响应饮食挑战而进展的巨噬细胞调节节点尚不完全清楚。肝脏 X 受体 (LXR) 是甾醇调节的转录因子，通过整合胆固醇稳态和免疫在动脉粥样硬化中发挥核心作用。 LXR 药理学激活可在巨噬细胞中引发强大的抗动脉粥样硬化转录程序，该程序可在体外受到 LXRa S196 磷酸化的影响。为了研究这些转录变化对动脉粥样硬化发展的影响，我们在 LDL 受体 (LDLR) 缺陷的动脉粥样硬化背景下培育了骨髓细胞中携带 Ser-Ala 突变的小鼠 (M-S196ALdlr-KO)。饲喂高脂肪饮食的 M-S196ALdlr-KO 小鼠表现出动脉粥样硬化斑块负担增加以及具有较小坏死核心和较薄纤维帽的病变。这些饮食引起的表型变化与动脉粥样硬化发展过程中 LXRa-S196A 促进的重编程巨噬细胞转录组一致。值得注意的是，LXRa-S196A 可诱导多种增殖促进因子的表达，包括原癌基因 FoxM1 及其靶标。这与 M-S196ALdlr-KO 小鼠中斑块驻留细胞增殖的增加一致。此外，破坏的 LXRa 磷酸化会增加吞噬分子的表达，导致巨噬细胞对凋亡细胞的清除增加，这解释了坏死核心的减少。最后，饮食扰动下 LXRa-S196A 促进的巨噬细胞转录组与 LXR 配体激活所揭示的巨噬细胞转录组明显不同，凸显了这种翻译后修饰的奇点。总的来说，我们的研究结果表明，LXRa 在 S196 上的磷酸化是通过影响多种途径的基因转录的选择性变化而成为动脉粥样硬化斑块发展的重要决定因素。
Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust anti-atherosclerotic transcriptional program in macrophages that can be affected by LXRa S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXRa-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXRa-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXRa phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXRa-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXRa phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.