Impaired mast cell maturation and degranulation and attenuated allergic responses in Ndrg1-deficient mice
Impaired mast cell maturation and degranulation and attenuated allergic responses in Ndrg1-deficient mice
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DOI：
10.4049/jimmunol.178.11.7042
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Kudo, Ichiro
中科院分区：
文献类型：
--
作者：
Taketomi, Yoshitaka;Sunaga, Kohei;Kudo, Ichiro
我们之前报道过，N-myc 下游调节基因 1 (NDRG1) 是小鼠骨髓源性肥大细胞 (BMMC) 向结缔组织肥大细胞样表型成熟过程中的早期诱导蛋白。为了阐明 NDRG1 在肥大细胞和过敏反应中的功能，我们分析了缺乏 Ndrg1 基因的小鼠肥大细胞相关表型。与野生型小鼠相比，Ndrg1 缺陷小鼠的过敏反应（包括 IgE 介导的被动全身和皮肤过敏反应）明显减弱。在 Ndrg1 缺陷小鼠中，真皮和腹膜肥大细胞数量减少，形态异常，脱颗粒能力受损。在干细胞因子存在下，Ndrg1 缺陷型 BMMC 与 Swiss 3T3 成纤维细胞共培养（一种促进 BMMC 向 CTMC 样表型成熟的条件），在 Fc epsilon RI 交联或用化合物 48/80 刺激后，表现出比复制野生型细胞更少的胞吐作用，尽管 IL-3 维持的胞吐反应，两种基因型的未成熟 BMMC 具有可比性。与脱颗粒不同，共培养的 BMMC 产生的白三烯和细胞因子不受 NDRG1 缺陷的影响。综上所述，Ndrg1 缺陷型肥大细胞在体内和体外的表型改变表明 NDRG1 在肥大细胞的终末成熟和效应功能（脱粒）中发挥作用。
We have previously reported that N-myc downstream regulated gene-1 (NDRG1) is an early inducible protein during the maturation of mouse bone marrow-derived mast cells (BMMCs) toward a connective tissue mast cell-like phenotype. To clarify the function of NDRG1 in mast cells and allergic responses, we herein analyzed mast cell-associated phenotypes of mice lacking the Ndrg1 gene. Allergic responses including IgE-mediated passive systemic and cutaneous anaphylactic reactions were markedly attenuated in Ndrg1 deficient mice as compared with those in wild-type mice. In Ndrg1-deficient mice, dermal and peritoneal mast cells were decreased in number and morphologically abnormal with impaired degranulating ability. Ex vivo, Ndrg1-deficient BMMCs cocultured with Swiss 3T3 fibroblasts in the presence of stem cell factor, a condition that facilitates the maturation of BMMCs toward a CTMC-like phenotype, displayed less exocytosis than replicate wild-type cells after the cross-linking of Fc epsilon RI or stimulation with compound 48/80, even though the exocytotic response of IL-3-maintained, immature BMMCs from both genotypes was comparable. Unlike degranulation, the production of leukotriene and cytokines by cocultured BMMCs was unaffected by NDRG1 deficiency. Taken together, the altered phenotypes of Ndrg1-deficient mast cells both in vivo and ex vivo suggest that NDRG1 has roles in the terminal maturation and effector function (degranulation) of mast cells.