Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1-/- Mice
Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1-/- Mice
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DOI：
10.4049/jimmunol.1004185
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发表时间：
2011-06-15
影响因子：
4.4
通讯作者：
Hibbs, Margaret L.
中科院分区：
文献类型：
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作者：
Maxwell, Mhairi J.;Duan, Mubing;Hibbs, Margaret L.
另一种激活的M2巨噬细胞被认为既是肺部疾病的调节者，也是肺部疾病的介质，但人们对其控制知之甚少。SHIP-1是一种5‘-肌醇磷酸酶，负向调节参与炎症反应的PI3K信号通路。SHIP-1基因缺陷的小鼠在造血和B细胞发育方面存在缺陷，并由于M2偏斜的巨噬细胞导致肺部固结而过早死亡。SHIP-1被认为抑制了M2巨噬细胞的极化，在SHIP-1缺陷的小鼠中，解除调控的M2偏斜与严重的肺部疾病相吻合。为了确定遗传背景对SHIP-1(-/-)小鼠肺表型的影响，我们将SHIP-1零突变与C57BL/6(Th2抗性)和BALB/c(Th2倾向)背景回交。值得注意的是，我们发现C57的炎症性肺病很严重。Ship-1(-/-)小鼠，但BALB中没有。Ship-1(-/-)小鼠。C57。SHIP-1(-/-)，但不是BALB。SHIP-1(-/-)小鼠髓系祖细胞明显增多，髓系增生，活化的肺泡巨噬细胞数显著增加，肺泡灌洗液和血清中Th2和促炎细胞因子的含量增加，提示细胞因子的产生失控导致疾病的发生。C57。SHIP1 2/2小鼠也出现严重的B细胞依赖性自身免疫性疾病，在BALB/c背景下明显减轻。这些数据表明，与目前的概念相反，SHIP-1的丢失本身不足以引起肺部炎症，疾病只在允许的遗传背景下表现出来。这一发现质疑了SHIP-1(-/-)小鼠肺部疾病的性质，表明其M2分类并不严格正确。未来对致病基因的识别可能会揭示肺部疾病和自身免疫的决定因素，并发现潜在的有用的治疗靶点。免疫学杂志，2011,186：7164-7175。
Alternatively activated M2 macrophages are implicated as both regulators and agents of lung disease, but their control is poorly understood. SHIP-1 is a 5 ' inositol phosphatase that negatively regulates the PI3K signaling pathway implicated in inflammation. SHIP-1-deficient mice have defects in hematopoiesis and B cell development, and die prematurely due to consolidation of lungs with M2-skewed macrophages. SHIP-1 is thought to restrain M2 macrophage polarization, with deregulated M2 skewing coinciding with severe lung disease in SHIP-1-deficient mice. To determine the influence of genetic background on the lung phenotype in SHIP-1(-/-) mice, we backcrossed the SHIP-1 null mutation onto C57BL/6 (Th2-resistant) and BALB/c (Th2prone) backgrounds. Remarkably, we found that inflammatory lung disease was severe in C57. SHIP-1(-/-) mice, but absent in BALB. SHIP-1(-/-) mice. C57. SHIP-1(-/-), but not BALB. SHIP-1(-/-) mice had greatly increased myeloid progenitors, myeloid hyperplasia, markedly enhanced numbers of activated alveolar macrophages, and elevated amounts of Th2 and proinflammatory cytokines in bronchoalveolar lavage fluid and serum, suggesting that deregulated cytokine production induced disease. C57. SHIP1 2/2 mice also developed severe B cell-dependent autoimmune disease, which was markedly attenuated on the BALB/c background. These data demonstrate that, contrary to current concepts, loss of SHIP-1 alone is not sufficient to cause lung inflammation, with disease only manifest on a permissive genetic background. This finding questions the nature of the lung disease in SHIP-1(-/-) mice, suggesting that its M2 classification is not strictly correct. Future identification of disease-promoting loci might reveal determinants of comorbid lung disease and autoimmunity and uncover potentially useful therapeutic targets. The Journal of Immunology, 2011, 186: 7164-7175.