PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium-Induced Colitis
PTPN22 Modulates Macrophage Polarization and Susceptibility to Dextran Sulfate Sodium-Induced Colitis
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DOI：
10.4049/jimmunol.1203363
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Ho, I-Cheng
中科院分区：
文献类型：
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作者：
Chang, Hui-Hsin;Miaw, Shi-Chuen;Ho, I-Cheng
PTPN22是一种主要在造血细胞中表达的蛋白酪氨酸磷酸酶，与许多自身免疫性疾病有关。人类PTPN22 cDNA 1858位的C-to-T单核苷酸多态性（SNP）可降低克罗恩病的风险。然而，PTPN22的功能以及该SNP降低克罗恩病风险的机制尚不清楚。我们发现PTPN22在巨噬细胞中表达。它抑制M1巨噬细胞极化，并相互促进m2相关基因的表达。ptpn22缺失小鼠发生葡聚糖硫酸钠诱导的严重结肠炎，其肠道巨噬细胞M1基因表达水平升高，m2相关基因表达水平降低。此外，C1858T SNP的保护性T等位基因与人M1巨噬细胞中炎症细胞因子的表达减弱和PTPN22水平升高有关。这种T等位基因相关的PTPN22异常表达部分归因于自身抑制机制，其中PTPN22抑制其自身在M1而非M2巨噬细胞中的表达。我们的数据不仅证明了PTPN22在调节巨噬细胞极化中的关键作用，而且还为C1858T SNP在克罗恩病中的保护作用提供了分子解释。
PTPN22, a protein tyrosine phosphatase expressed mainly in hematopoietic cells, has been linked to many autoimmune diseases. A C-to-T single nucleotide polymorphism (SNP) at position 1858 of human PTPN22 cDNA decreases the risk of Crohn's disease. However, the function of PTPN22 and the mechanism by which this SNP reduces the risk of Crohn's disease are poorly understood. We find that PTPN22 is expressed in macrophages. It suppresses M1 macrophage polarization and reciprocally promotes the expression of M2-associated genes. PTPN22-deficient mice develop severe colitis induced by dextran sulfate sodium, and their intestinal macrophages express higher levels of M1 genes but lower levels of M2-associated genes. Furthermore, the protective T allele of the C1858T SNP is associated with attenuated expression of inflammatory cytokines and a higher level of PTPN22 in human M1 macrophages. This T allele-associated aberrant expression of PTPN22 is partly attributed to an auto-inhibition mechanism, in which PTPN22 suppresses its own expression in M1 but not M2 macrophages. Our data not only demonstrate a critical role of PTPN22 in regulating macrophage polarization but also provide a molecular explanation for the protective effect of the C1858T SNP in Crohn's disease.