Department of Laboratory Medicine and the Program in Immunology, University of California, San Francisco 94143, USA.
Immunity. 2013 Mar 21;38(3):489-501. doi: 10.1016/j.immuni.2013.02.018.
The motheaten mouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations in Ptpn6, which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause the motheaten phenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell types, so the cellular and molecular mechanism of autoimmunity and inflammation in the motheaten mouse has remained unclear. By using floxed Ptpn6 mice, we dissected the contribution of innate immune cells to the motheaten phenotype. Ptpn6 deletion in neutrophils resulted in cutaneous inflammation, but not autoimmunity, providing an animal model of human neutrophilic dermatoses. By contrast, dendritic cell deletion caused severe autoimmunity, without inflammation. Genetic and biochemical analysis showed that inflammation was caused by enhanced neutrophil integrin signaling through Src-family and Syk kinases, whereas autoimmunity resulted from exaggerated MyD88-dependent signaling in dendritic cells. Our data demonstrate that disruption of distinct Shp1-regulated pathways in different cell types combine to cause motheaten disease.
斑驳鼠长期以来一直是复杂自身免疫和炎症性疾病的典范。编码非受体蛋白酪氨酸磷酸酶 Shp1 的 Ptpn6 发生无义突变会导致斑驳表型。然而，Shp1 在不同的造血细胞类型中调节多种信号通路，因此斑驳鼠自身免疫和炎症的细胞和分子机制仍不清楚。通过使用 floxed Ptpn6 小鼠，我们剖析了固有免疫细胞对斑驳表型的贡献。中性粒细胞中的 Ptpn6 缺失导致皮肤炎症，但不引起自身免疫，为人类中性粒细胞皮肤病提供了一个动物模型。相比之下，树突状细胞缺失导致严重的自身免疫，而没有炎症。遗传和生化分析表明，炎症是通过Src 家族和 Syk 激酶增强中性粒细胞整合素信号引起的，而自身免疫则是由于树突状细胞中 MyD88 依赖性信号的过度放大引起的。我们的数据表明，不同细胞类型中不同 Shp1 调节途径的破坏结合在一起导致斑驳病的发生。
