Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease
Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease
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DOI：
10.1182/blood-2005-09-3556
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发表时间：
2006-04-15
期刊：
影响因子：
20.3
通讯作者：
Stanley, ER
中科院分区：
文献类型：
--
作者：
Grosse, J;Chitu, V;Stanley, ER
巨噬细胞肌动蛋白相关酪氨酸磷酸化蛋白(MAYP)/PSTPIP2是一种PCH蛋白，参与巨噬细胞运动的调节。一种密切相关的基因PSTP1P1/CD2BP1的突变会导致一种被称为Papa综合征的显性遗传性自体炎症疾病。通过化学诱变获得的突变小鼠表现出以巨噬细胞浸润和炎症为特征的自体炎症障碍，导致爪骨溶解和坏死，以及耳朵的坏死。对这种隐性突变的定位克隆，称为Lupo，发现了导致Mayr Mayp(LP/LP)病序列中氨基酸替换(1282N)的T-A核苷酸交换，该突变可通过骨髓移植转移，并在没有淋巴细胞的情况下发育。与巨噬细胞的参与一致，病变的发展可以通过给药屈光酸脂质体来阻止。MAYP表达于单核/巨噬细胞和粒细胞MAC1(+)亚组分。内毒素刺激可增加其在巨噬细胞中的表达。由于突变蛋白的不稳定性，MAYP在Mayp(LP/LP)巨噬细胞中的表达减少了3倍，在内毒素刺激下，MAYP的表达不会上升到未刺激的野生型(WT)细胞的水平。Mayp(LP/LP)小鼠循环中多种细胞因子水平升高，包括MCP-1；它们的巨噬细胞在体外表现出细胞因子产生的改变。这些研究表明，MAYP在巨噬细胞中具有抗炎作用。
Macrophage actin-associated tyrosine phosphorylated protein (MAYP)/PSTPIP2, a PCH protein, is involved in the regulation of macrophage motility. Mutations in a closely related gene, PSTP1P1/CD2BP1, cause a dominantly inherited autoinflammatory disorder known as PAPA syndrome. A mutant mouse obtained by chemical mutagenesis exhibited an autoinflammatory disorder characterized by macrophage infiltration and inflammation, leading to osteolysis and necrosis in paws and necrosis of ears. Positional cloning of this recessive mutation, termed Lupo, identified a T to A nucleotide exchange leading to an amino acid substitution (1282N) in the sequence of MAYR Mayp(LP/LP) disease was transferable by bone marrow transplantation and developed in the absence of lymphocytes. Consistent with the involvement of macrophages, lesion development could be prevented by the administration of dronate liposomes. MAYP is expressed in monocytes/macrophages and in a Mac1(+) subfraction of granulocytes. LPS stimulation increases its expression in macrophages. Because of the instability of the mutant protein, MAYP expression is reduced 3-fold in Mayp(LP/LP) macrophages and, on LPS stimulation, does not rise above the level of unstimulated wild-type (WT) cells. Mayp(LP/LP) mice expressed elevated circulating levels of several cytokines, including MCP-1; their macrophages exhibited altered cytokine production in vitro. These studies suggest that MAYP plays an anti-inflammatory role in macrophages.