JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages
JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages
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DOI：
10.1016/j.ejphar.2020.172940
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发表时间：
2020-03-15
影响因子：
5
通讯作者：
Katoh, Youichi
中科院分区：
文献类型：
--
作者：
Hashimoto, Ryota;Kakigi, Ryo;Katoh, Youichi
在动脉粥样硬化进展中，动脉粥样硬化斑块在来自巨噬细胞的积累的泡沫细胞上发展，所述泡沫细胞摄取修饰的低密度脂蛋白（LDL）。CD 36和CD 204是负责摄取修饰的LDL的主要清道夫受体。脂多糖（LPS）通过增强清道夫受体的表达，从而增加巨噬细胞对修饰的LDL的摄取，从而加剧动脉粥样硬化。然而，介导LPS和清道夫受体表达的信号通路尚未完全阐明。LPS可增强细胞外信号调节激酶（ERK）和信号转导和转录激活因子-1（STAT-1）的磷酸化。丝裂原活化蛋白激酶（MAPK）/ERK激酶（MEK）通路抑制剂（U 0126和PD 0325901）抑制LPS激活的巨噬细胞中乙酰化LDL（Ac-LDL）的摄取和CD 204的表达，但不抑制CD 36的表达。Janus酪氨酸激酶（JAK）-STAT通路抑制剂（ruxolitinib和tofacitinib）可抑制LPS激活的巨噬细胞中Ac-LDL的摄取以及CD 36和CD 204的表达。接下来，我们将LPS注射到小鼠的腹膜腔中并分析LPS的作用。MEK抑制剂U 0126可抑制LPS激活的巨噬细胞对Ac-LDL的摄取和CD 204的表达，但对CD 36的表达无影响。JAK抑制剂ruxolitinib抑制LPS激活的巨噬细胞中Ac-LDL的摄取以及CD 36和CD 204的表达。这些结果表明，LPS激活的小鼠巨噬细胞中的清道夫受体通过JAK-STAT依赖性途径进行调节。尽管还需要进一步的评估，JAK-STAT抑制在动脉粥样硬化治疗中可能是有用的，至少对于LPS加重的动脉粥样硬化是有用的。
In atherosclerosis progression, atherosclerotic plaques develop upon accumulated foam cells derived from macrophages that take up modified low-density lipoprotein (LDL). CD36 and CD204 are the principal scavenger receptors responsible for the uptake of modified LDL. Lipopolysaccharide (LPS) exacerbates atherosclerosis by enhancing the expression of scavenger receptors and thus increasing the uptake of modified LDL into macrophages. However, the signaling pathways that mediate LPS and scavenger receptor expression have not been fully elucidated.We used mouse bone marrow-derived macrophages and investigated the effects of LPS in vitro. LPS enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-1 (STAT-1). Inhibitors of the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) pathway (U0126 and PD0325901) suppressed the uptake of acetylated-LDL (Ac-LDL) and the expression of CD204 but not CD36 in LPS-activated macrophages. Inhibitors of the Janus tyrosine kinase (JAK)-STAT pathway (ruxolitinib and tofacitinib) suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. We next injected LPS into the peritoneal cavity of mice and analyzed the effects of LPS. MEK inhibitor U0126 suppressed the uptake of Ac-LDL and the expression of CD204 but not CD36 in LPS-activated macrophages. JAK inhibitor ruxolitinib suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. These results suggest that scavenger receptors in LPS-activated mouse macrophages are regulated through a JAK-STAT-dependent pathway. Although further evaluation is necessary, JAK-STAT inhibition could be useful in atherosclerosis therapy, at least for atherosclerosis exacerbated by LPS.