MEK inhibition exerts temporal and myeloid cell-specific effects in the pathogenesis of neurofibromatosis type 1 arteriopathy.
MEK inhibition exerts temporal and myeloid cell-specific effects in the pathogenesis of neurofibromatosis type 1 arteriopathy.
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DOI：
10.1038/s41598-021-03750-6
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发表时间：
2021-12-21
影响因子：
4.6
通讯作者：
Stansfield BK
中科院分区：
文献类型：
--
作者：
Tritz R;Hudson FZ;Harris V;Ghoshal P;Singla B;Lin H;Csanyi G;Stansfield BK
NF 1肿瘤抑制基因的突变与动脉病有关。Nf 1杂合性（Nf 1 +/-）导致稳健的新生内膜形成，与人类相似，骨髓限制性Nf 1 +/-通过MEK-ERK激活重现了该表型。在这里，我们定义的髓细胞亚群的贡献NF 1动脉病变。在存在MEK和法尼基化抑制剂的情况下，在体外对WT和Nf 1 +/-小鼠的中性粒细胞进行功能评估，并在WT和Nf 1 +/-小鼠中评估中性粒细胞向脂多糖的募集。对同窝出生的12-15周龄雄性野生型和Nf 1 +/-小鼠进行颈动脉结扎，并提供嗜中性粒细胞消耗抗体（1A 8）、脂质体氯膦酸盐以消耗单核细胞/巨噬细胞或PD 0325901，并在损伤后28天评估新生内膜尺寸。骨髓移植实验评估了新生内膜形成过程中单核细胞/巨噬细胞的动员。Nf 1 +/-中性粒细胞通过p21 Ras激活MEK在体外和体内表现出增强的增殖、迁移和粘附。中性粒细胞耗竭抑制循环Ly 6Clow单核细胞并增加新生内膜大小，而单核细胞/巨噬细胞耗竭和骨髓细胞中CCR 2的缺失消除了Nf 1 +/-小鼠中的新生内膜形成。总之，这些发现表明，在动脉重塑过程中，循环中性粒细胞和单核细胞中的神经纤维蛋白酶-MEK-ERK激活是微妙的，并指出这些人群之间的重要串扰在NF 1动脉病的发病机制。
Mutations in the NF1 tumor suppressor gene are linked to arteriopathy. Nf1 heterozygosity (Nf1+/–) results in robust neointima formation, similar to humans, and myeloid-restricted Nf1+/– recapitulates this phenotype via MEK-ERK activation. Here we define the contribution of myeloid subpopulations to NF1 arteriopathy. Neutrophils from WT and Nf1+/– mice were functionally assessed in the presence of MEK and farnesylation inhibitors in vitro and neutrophil recruitment to lipopolysaccharide was assessed in WT and Nf1+/– mice. Littermate 12–15 week-old male wildtype and Nf1+/– mice were subjected to carotid artery ligation and provided either a neutrophil depleting antibody (1A8), liposomal clodronate to deplete monocytes/macrophages, or PD0325901 and neointima size was assessed 28 days after injury. Bone marrow transplant experiments assessed monocyte/macrophage mobilization during neointima formation. Nf1+/– neutrophils exhibit enhanced proliferation, migration, and adhesion via p21Ras activation of MEK in vitro and in vivo. Neutrophil depletion suppresses circulating Ly6Clow monocytes and enhances neointima size, while monocyte/macrophage depletion and deletion of CCR2 in bone marrow cells abolish neointima formation in Nf1+/– mice. Taken together, these findings suggest that neurofibromin-MEK-ERK activation in circulating neutrophils and monocytes during arterial remodeling is nuanced and points to important cross-talk between these populations in the pathogenesis of NF1 arteriopathy.
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影响因子：
15.9
作者：
Lasater, Elisabeth A.;Li, Fang;Ingram, David A., Jr.
通讯作者：
Ingram, David A., Jr.
影响因子：
14.5
作者：
Mildner, Alexander;Mack, Matthias;Prinz, Marco
通讯作者：
Prinz, Marco
影响因子：
19.6
作者：
Giunti, S;Pinach, S;Gruden, G
通讯作者：
Gruden, G
影响因子：
3.6
作者：
Prame Kumar K;Nicholls AJ;Wong CHY
通讯作者：
Wong CHY
影响因子：
37.8
作者：
Combadiere, Christophe;Potteaux, Stephane;Mallat, Ziad
通讯作者：
Mallat, Ziad