Long-term glucocorticoid treatment increases CD204 expression by activating the MAPK pathway and enhances modified LDL uptake in murine macrophages
Long-term glucocorticoid treatment increases CD204 expression by activating the MAPK pathway and enhances modified LDL uptake in murine macrophages
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长期糖皮质激素治疗通过激活 MAPK 途径增加 CD204 表达并增强小鼠巨噬细胞中修饰的 LDL 摄取
DOI：
10.1016/j.jphs.2022.11.003
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发表时间：
2023
影响因子：
3.5
通讯作者：
Katoh-Y
中科院分区：
文献类型：
--
作者：
Hashimoto-R;Koide-H;Katoh-Y
动脉粥样硬化斑块是巨噬细胞来源的泡沫细胞通过摄取改性低密度脂蛋白（LDL）积累而形成的。CD36和CD204是负责摄取修饰LDL的主要清道夫受体。虽然糖皮质激素被怀疑会加剧动脉粥样硬化，但其确切机制尚未完全阐明。我们采用流式细胞术和western blotting研究了天然糖皮质激素（氢化可的松，HC, 1 μM）和合成糖皮质激素（地塞米松，Dex, 100 nM）长期治疗（2周）对小鼠骨髓源性巨噬细胞的影响。HC和Dex治疗可增强CD204表达，但不能增强CD36表达和乙酰化LDL （Ac-LDL）摄取。HC和Dex也能诱导细胞外信号调节激酶（ERK）的磷酸化。一种丝裂原活化蛋白激酶(MAPK)/ERK激酶抑制剂抑制了dex诱导的CD204表达增强和Ac-LDL摄取。这些结果表明糖皮质激素激活MAPK/ERK通路，从而增强CD204的表达并导致巨噬细胞对Ac-LDL的摄取增加。巨噬细胞中的MAPK/ERK通路可能是预防糖皮质激素恶化的动脉粥样硬化的关键靶点。
Atherosclerotic plaques develop from the accumulation of macrophage-derived foam cells via the uptake of modified low-density lipoprotein (LDL). CD36 and CD204 are the principal scavenger receptors responsible for the uptake of modified LDL. Although glucocorticoids are suspected to exacerbate atherosclerosis, the precise mechanisms have not been fully elucidated. We investigated the effects of long-term treatment (2 weeks) with both a natural glucocorticoid (hydrocortisone, HC, 1 μM) and a synthetic glucocorticoid (dexamethasone, Dex, 100 nM) on murine bone marrow-derived macrophages using flow cytometry and western blotting. Treatment with HC and Dex enhanced CD204 expression but not CD36 expression and acetylated LDL (Ac-LDL) uptake. Treatment with HC and Dex also induced the phosphorylation of extracellular signal-regulated kinase (ERK). The Dex-induced enhancement in CD204 expression and Ac-LDL uptake were suppressed by an inhibitor of the mitogen-activated protein kinase (MAPK)/ERK kinase. These results suggest that glucocorticoids activate the MAPK/ERK pathway, which enhances CD204 expression and results in increased uptake of Ac-LDL in macrophages. The MAPK/ERK pathway in macrophages might be a key target to prevent atherosclerosis that is worsened by glucocorticoids.