Lots of studies demonstrated that CD4+ T cells regulate the development of atherosclerosis (AS). Previously, we reported that LCK, a key molecule in activation of T cell receptor (TCR) signalling and T cells, adversely affects reverse cholesterol transport (RCT), which ameliorates AS in vitro. To investigate the effect of LCK on AS in vivo, we injected the LCK inhibitor, PP2, into ApoE-/- mice fed a chow diet or a high-fat diet (HFD). Although, AS plaques were not affected by PP2 in chow diet-fed mice, PP2 significantly reduced the lesion percentage and necrotic core areas in HFD-fed mice. We further analysed the plaque contents and found that the accumulation of lipids and macrophages were decreased, while the contents of collagen and smooth muscle cells were increased by the LCK inhibitor. Thus, inhibiting LCK enhanced the plaque stability. We also found the LCK inhibitor improved cholesterol efflux capacity of HDL and up-regulated RCT regulatory proteins in the spleen. Moreover, inhibiting LCK regulated differentiation of T cells by increasing regulatory T (Treg) cells and decreasing the number of T helper 1 (Th1) cells in the aorta, thymus and spleen. Consistent with these results, infiltration of CD4+ T cells in plaques, secretion of pro-atherosclerotic cytokines, INF-γ and TNF-α synthesized mostly by Th1 cells, and the activation of PI3K/AKT/mTOR signalling were inhibited by the LCK inhibitor. Moreover, the effect of LCK inhibitor on the ratio of Th1 to Treg cells were compromised by activation of mTOR. Together, these data indicate that inhibiting LCK in TCR signalling attenuated the development of AS and promoted plaque stability. Improving RCT by upregulating RCT regulatory proteins and decreasing the Th1/Treg ratio by inhibiting PI3K/AKT/mTOR signalling may contribute to the anti-atherosclerotic effects of LCK inhibition.

中文翻译：

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LCK抑制剂通过调节T细胞分化和逆向胆固醇转运来减轻ApoE-/-小鼠的动脉粥样硬化。

许多研究表明，CD4 + T细胞可调节动脉粥样硬化（AS）的发展。以前，我们报道了LCK是激活T细胞受体（TCR）信号和T细胞的关键分子，它对胆固醇逆向转运（RCT）产生不利影响，从而改善了AS的体外作用。为了研究LCK在体内对AS的影响，我们将LCK抑制剂PP2注射到喂了日常饮食或高脂饮食（HFD）的ApoE-/-小鼠中。尽管在日常饮食喂养的小鼠中AS斑块不受PP2的影响，但PP2显着降低了由HFD喂养的小鼠的病变百分比和坏死核心区域。我们进一步分析了斑块含量，发现脂质和巨噬细胞的积累减少了，而LCK抑制剂增加了胶原和平滑肌细胞的含量。因此，抑制LCK增强了斑块稳定性。我们还发现，LCK抑制剂可改善HDL的胆固醇外排能力，并改善脾脏中的RCT调节蛋白。此外，通过增加主动脉，胸腺和脾脏中的调节性T（Treg）细胞并减少T辅助1（Th1）细胞的数量来抑制LCK调节T细胞的分化。与这些结果一致的是，LCK抑制剂抑制了斑块中CD4 + T细胞的浸润，动脉粥样硬化细胞因子的分泌，Th1细胞主要合成的INF-γ和TNF-α以及PI3K / AKT / mTOR信号的激活。而且，LCK抑制剂对Th1与Treg细胞之比的作用被mTOR的激活所损害。总之，这些数据表明，抑制TCR信号传导中的LCK会减弱AS的发展并促进斑块稳定性。