PDF(Pubmed)
Abstract：
Inhibition of STAT5 was recently reported to reduce murine atherosclerosis. However, the role of STAT5 isoforms, and more in particular STAT5A in macrophages in the context of human atherosclerosis remains unknown.
Here, we demonstrate reciprocal expression regulation of STAT5A and STAT5B in human atherosclerotic lesions. The former was highly upregulated in ruptured over stable plaque and correlated with macrophage presence, a finding that was corroborated by the high chromosomal accessibility of STAT5A but not B gene in plaque macrophages. Phosphorylated STAT5 correlated with macrophages confirming its activation status. As macrophage STAT5 is activated by GM-CSF, we studied the effects of its silencing in GM-CSF differentiated human macrophages. STAT5A knockdown blunted the immune response, phagocytosis, cholesterol metabolism, and augmented apoptosis terms on transcriptional levels. These changes could partially be confirmed at functional level, with significant increases in apoptosis and decreases in lipid uptake and IL-6, IL-8, and TNFa cytokine secretion after STAT5A knockdown. Finally, inhibition of general and isoform A specific STAT5 significantly reduced the secretion of TNFa, IL-8 and IL-10 in ex vivo tissue slices of advanced human atherosclerotic plaques.
In summary, we identify STAT5A as an important determinant of macrophage functions and inflammation in the context of atherosclerosis and show its promise as therapeutic target in human atherosclerotic plaque inflammation.
Here, we demonstrate reciprocal expression regulation of STAT5A and STAT5B in human atherosclerotic lesions. The former was highly upregulated in ruptured over stable plaque and correlated with macrophage presence, a finding that was corroborated by the high chromosomal accessibility of STAT5A but not B gene in plaque macrophages. Phosphorylated STAT5 correlated with macrophages confirming its activation status. As macrophage STAT5 is activated by GM-CSF, we studied the effects of its silencing in GM-CSF differentiated human macrophages. STAT5A knockdown blunted the immune response, phagocytosis, cholesterol metabolism, and augmented apoptosis terms on transcriptional levels. These changes could partially be confirmed at functional level, with significant increases in apoptosis and decreases in lipid uptake and IL-6, IL-8, and TNFa cytokine secretion after STAT5A knockdown. Finally, inhibition of general and isoform A specific STAT5 significantly reduced the secretion of TNFa, IL-8 and IL-10 in ex vivo tissue slices of advanced human atherosclerotic plaques.
In summary, we identify STAT5A as an important determinant of macrophage functions and inflammation in the context of atherosclerosis and show its promise as therapeutic target in human atherosclerotic plaque inflammation.
摘要：
■最近报道了抑制STAT5可减少鼠动脉粥样硬化。然而,STAT5亚型的作用，更特别是在人动脉粥样硬化的情况下巨噬细胞中的STAT5A仍然未知。
■这里，我们证明了人动脉粥样硬化病变中STAT5A和STAT5B的相互表达调控.前者在稳定斑块上破裂时高度上调，并与巨噬细胞的存在相关，这一发现由斑块巨噬细胞中STAT5A而不是B基因的高染色体可接近性证实。磷酸化STAT5与巨噬细胞相关,证实其活化状态。当巨噬细胞STAT5被GM-CSF激活时，我们研究了其沉默对GM-CSF分化的人巨噬细胞的影响.STAT5A敲低减弱了免疫反应，吞噬作用,胆固醇代谢，和转录水平上增加的凋亡术语。这些变化可以在功能层面得到部分确认，STAT5A敲低后，细胞凋亡显着增加，脂质摄取和IL-6，IL-8和TNFα细胞因子分泌减少。最后,一般和同工型A特异性STAT5的抑制显着降低了TNFα的分泌，晚期人动脉粥样硬化斑块的离体组织切片中的IL-8和IL-10。
■总之，我们确定STAT5A是动脉粥样硬化背景下巨噬细胞功能和炎症的重要决定因素,并显示其有望作为人类动脉粥样硬化斑块炎症的治疗靶点.
■这里，我们证明了人动脉粥样硬化病变中STAT5A和STAT5B的相互表达调控.前者在稳定斑块上破裂时高度上调，并与巨噬细胞的存在相关，这一发现由斑块巨噬细胞中STAT5A而不是B基因的高染色体可接近性证实。磷酸化STAT5与巨噬细胞相关,证实其活化状态。当巨噬细胞STAT5被GM-CSF激活时，我们研究了其沉默对GM-CSF分化的人巨噬细胞的影响.STAT5A敲低减弱了免疫反应，吞噬作用,胆固醇代谢，和转录水平上增加的凋亡术语。这些变化可以在功能层面得到部分确认，STAT5A敲低后，细胞凋亡显着增加，脂质摄取和IL-6，IL-8和TNFα细胞因子分泌减少。最后,一般和同工型A特异性STAT5的抑制显着降低了TNFα的分泌，晚期人动脉粥样硬化斑块的离体组织切片中的IL-8和IL-10。
■总之，我们确定STAT5A是动脉粥样硬化背景下巨噬细胞功能和炎症的重要决定因素,并显示其有望作为人类动脉粥样硬化斑块炎症的治疗靶点.
