PDF(Pubmed)
Abstract：
UNASSIGNED: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis.
UNASSIGNED: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet-fed ApoE -/- mice or PCSK9mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6-/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6\'s role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells.
UNASSIGNED: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis.
UNASSIGNED: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet-fed ApoE -/- mice or PCSK9mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6-/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6\'s role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells.
UNASSIGNED: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis.
摘要：
CC趋化因子配体18(CCL18)是在人类慢性炎症中高度表达的趋化因子。最近对急性心血管综合征患者血浆CCL18水平升高的观察促使人们对CCL18在人和小鼠动脉粥样硬化发病机理中的作用进行了研究。
■CCL18在破裂的人动脉粥样硬化斑块中明显上调，特别是在巨噬细胞内。在Western型饮食喂养的ApoE-/-小鼠或PCSK9mut过表达的野生型（WT）小鼠中重复施用CCL18导致斑块负荷增加，富含CD3+T细胞。在随后的实验和分子建模研究中，我们确定CCR6是介导CCL18趋化性的功能性受体，细胞内Ca2+通量，以及人Jurkat和小鼠T细胞中的下游信号传导。CCL18未能在具有CCR6缺乏的鼠脾T细胞中体外诱导这些作用。CCR6作为CCL18受体的能力在体内炎症模型中得到证实，其中皮下CCL18注射在WT中引起深度局灶性皮肤炎症,但在CCR6-/-小鼠中没有。这种炎症表现为水肿和各种白细胞亚群的明显浸润，包括带有Th17信号的T细胞,支持CCR6作为Th17趋化受体的作用。值得注意的是,斑块中CCL18的局灶性过表达与CCR6+(T)细胞的存在增加相关.
■我们的研究首次确定CCL18/CCR6轴是晚期鼠类和人类动脉粥样硬化中免疫反应的调节剂。
■CCL18在破裂的人动脉粥样硬化斑块中明显上调，特别是在巨噬细胞内。在Western型饮食喂养的ApoE-/-小鼠或PCSK9mut过表达的野生型（WT）小鼠中重复施用CCL18导致斑块负荷增加，富含CD3+T细胞。在随后的实验和分子建模研究中，我们确定CCR6是介导CCL18趋化性的功能性受体，细胞内Ca2+通量，以及人Jurkat和小鼠T细胞中的下游信号传导。CCL18未能在具有CCR6缺乏的鼠脾T细胞中体外诱导这些作用。CCR6作为CCL18受体的能力在体内炎症模型中得到证实，其中皮下CCL18注射在WT中引起深度局灶性皮肤炎症,但在CCR6-/-小鼠中没有。这种炎症表现为水肿和各种白细胞亚群的明显浸润，包括带有Th17信号的T细胞,支持CCR6作为Th17趋化受体的作用。值得注意的是,斑块中CCL18的局灶性过表达与CCR6+(T)细胞的存在增加相关.
■我们的研究首次确定CCL18/CCR6轴是晚期鼠类和人类动脉粥样硬化中免疫反应的调节剂。
