Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation
Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation
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DOI：
10.1093/hmg/ddv635
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发表时间：
2016-03-15
影响因子：
3.5
通讯作者：
Stansfield, Brian K.
中科院分区：
文献类型：
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作者：
Bessler, Waylan K.;Kim, Grace;Stansfield, Brian K.
患有1型神经纤维瘤病（NF 1）的人有过早和严重动脉狭窄的倾向。NF 1基因突变导致p21（Ras）负调节因子神经纤维蛋白表达降低，并增加Ras信号传导。杂合子Nf 1（Nf 1（+/-））小鼠出现明显的动脉狭窄，其特征为平滑肌细胞（SMC）增殖和浸润性巨噬细胞占优势，这与NF 1患者的动脉病变非常相似。有趣的是，单核细胞/巨噬细胞中单个Nf 1等位基因的谱系限制性失活足以概括Nf 1（+/-）小鼠中观察到的表型，并将促炎性CCR 2+单核细胞动员到外周血中。因此，我们假设CCR 2受体通过其主要配体单核细胞趋化蛋白-1（MCP-1）激活对于Nf 1（+/-）小鼠中单核细胞浸润到动脉壁和新生内膜形成至关重要。MCP-1诱导Nf 1（+/-）巨噬细胞迁移和增殖的剂量响应性增加，这与多种Ras激酶的激活相对应。此外，与WT SMC相比，表达CCR 2的Nf 1（+/-）SMC表现出对MCP-1的增强的增殖反应。为了探究CCR 2激活对Nf 1（+/-）新生内膜形成的作用，我们通过颈动脉结扎诱导MCP 1或CCR 2基因缺失的Nf 1（+/-）和WT小鼠的新生内膜形成。MCP-1或CCR 2表达的缺失有效地抑制了Nf 1（+/-）新生内膜的形成，并减少了动脉壁中的巨噬细胞含量。最后，给予CCR 2拮抗剂显著减少Nf 1（+/-）新生内膜形成。这些研究确定MCP-1是Nf 1（+/-）单核细胞/巨噬细胞的有效趋化因子，CCR 2是Nf 1动脉狭窄的可行治疗靶点。
Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.