Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice
Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice
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DOI：
10.1182/blood-2009-02-204925
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发表时间：
2009-09-17
期刊：
影响因子：
20.3
通讯作者：
Stanley, E. Richard
中科院分区：
文献类型：
--
作者：
Chitu, Violeta;Ferguson, Polly J.;Stanley, E. Richard
小鼠脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白2（PSTPIP 2）中的Lupo（I282 N）突变导致与巨噬细胞介导的自身炎症性疾病相关的PSTPIP 2表达减少。PSTPIP 2中的另一种突变L98 P，称为慢性多灶性骨髓炎（cmo），导致小鼠患上一种类似于人类慢性复发性多灶性骨髓炎的疾病。探讨了cmo病的细胞学基础。CMO疾病的发展不依赖于淋巴细胞，并可通过骨髓移植治愈。来自cmo小鼠的巨噬细胞、肥大细胞和破骨细胞不能表达可检测的PSTPIP 2蛋白。无症状Pstpip 2（cmo/cmo）小鼠具有增加的巨噬细胞炎性蛋白1-α和白介素-6的循环水平，并且它们的巨噬细胞表现出这些炎性介质的增加的产生，其通过野生型PSTPIP 2的逆转录病毒表达而正常化。无症状的cmo小鼠的脾脏含有增加数量的巨噬细胞前体，并且cmo小鼠对无菌炎症刺激的反应动员了更多的巨噬细胞前体。信号转导和转录激活因子1在cmo脾巨噬细胞中升高，这也表现出集落刺激因子1刺激的增殖增加和细胞外信号调节激酶1/2磷酸化增加。PSTPIP 2在巨噬细胞中的过表达导致相反的表型。因此，PSTPIP 2缺陷导致巨噬细胞祖细胞的扩增和成熟巨噬细胞对活化刺激的反应性增加，这两者一起引发生物体产生过度和持续的反应，导致自身炎性疾病。（血。2009; 114：2497-2505）
The mouse Lupo (I282N) mutation in proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) leads to reduced expression of PSTPIP2 that is associated with a macrophage-mediated autoinflammatory disease. Another mutation in PSTPIP2, L98P, termed chronic multifocal osteomyelits (cmo), leads to a disease in mice that resembles chronic recurrent multifocal osteomyelits in humans. The cellular basis of cmo disease was investigated. cmo disease develops independently of lymphocytes and is cured by bone marrow transplantation. Macrophages, mast cells, and osteoclasts from cmo mice fail to express detectable PSTPIP2 protein. Asymptomatic Pstpip2(cmo/cmo) mice have increased circulating levels of macrophage inflammatory protein 1-alpha and interleukin-6, and their macrophages exhibit increased production of these inflammatory mediators, which is normalized by retroviral expression of wild-type PSTPIP2. Spleens of asymptomatic cmo mice contain increased numbers of macrophage precursors, and cmo mice mobilize more macrophage precursors in response to a sterile inflammatory stimulus. Signal transducer and activator of transcription 1 is elevated in cmo splenic macrophages, which also exhibit increased colony-stimulating factor-1-stimulated proliferation and increased extracellular signal-regulated kinase 1/2 phosphorylation. PSTPIP2 overexpression in macrophages leads to the opposite phenotype. Thus, PSTPIP2 deficiency causes both an expansion of macrophage progenitors and increased responsiveness of mature macrophages to activating stimuli, which together prime the organism for exaggerated and sustained responses leading to autoinflammatory disease. (Blood. 2009; 114: 2497-2505)