Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis.
Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis.
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DOI：
10.1016/j.jaci.2011.02.005
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Theoharides TC
中科院分区：
文献类型：
--
作者：
Zhang B;Alysandratos KD;Angelidou A;Asadi S;Sismanopoulos N;Delivanis DA;Weng Z;Miniati A;Vasiadi M;Katsarou-Katsari A;Miao B;Leeman SE;Kalogeromitros D;Theoharides TC
肥大细胞来源于造血细胞前体，参与组织过敏、免疫和炎症过程。它们分泌许多介质，包括预先形成的TNF，以响应过敏、神经肽和环境触发。然而，肥大细胞脱颗粒的调节还不清楚。我们研究了线粒体动力学在人肥大细胞脱颗粒中的作用。用共聚焦显微镜和微分干涉显微镜观察了人脐带血来源的肥大细胞（hCBMCs）和过敏性疾病实验室2（LAD 2）肥大细胞在IgE/抗原和P物质（SP）激活过程中的变化。肥大细胞在对照和特应性皮炎（AD）皮肤进行了评估，通过透射电子显微镜。用线粒体分裂抑制剂、动力蛋白相关蛋白1（Drp 1）抑制剂和针对Drp 1的小干扰RNA预处理LAD 2细胞，所述小干扰RNA是线粒体分裂和易位所必需的。在刺激的LAD 2细胞和AD皮肤活检中分析钙调神经磷酸酶和Drp 1基因表达。用IgE/抗原刺激hCBMCs或用SP刺激LAD 2细胞导致预先形成的TNF的快速（30分钟）分泌。脱粒伴随着线粒体从核周位置到胞吐部位的移位。细胞外钙耗竭防止这些影响，表明钙的需求。钙依赖性钙调神经磷酸酶和Drp 1在SP刺激后30分钟被激活。通过线粒体分裂抑制剂降低Drp 1活性和使用小干扰RNA降低Drp 1表达抑制线粒体易位、脱粒和TNF分泌。线粒体易位也是明显的，通过透射电子显微镜在皮肤肥大细胞从AD活检，其中钙调神经磷酸酶，Drp 1和SP的基因表达高于正常皮肤。人肥大细胞脱粒需要线粒体动力学，也与AD有关。（J Allergy Clin Immunol 2011;127：1522-31.）
Mast cells derive from hematopoietic cell precursors and participate in tissue allergic, immune, and inflammatory processes. They secrete many mediators, including preformed TNF, in response to allergic, neuropeptide, and environmental triggers. However, regulation of mast cell degranulation is not well understood. We investigated the role of mitochondrial dynamics in degranulation of human cultured mast cells. Human umbilical cord blood–derived mast cells (hCBMCs) and Laboratory of Allergic Diseases 2 (LAD2) mast cells were examined by confocal and differential interference contrast microscopy during activation by IgE/antigen and substance P (SP). Mast cells in control and atopic dermatitis (AD) skin were evaluated by transmission electron microscopy. LAD2 cells were pretreated with mitochondrial division inhibitor, a dynamin-related protein 1 (Drp1) inhibitor, and small interfering RNA for Drp1, which is necessary for mitochondrial fission and translocation. Calcineurin and Drp1 gene expression was analyzed in stimulated LAD2 cells and AD skin biopsies. Stimulation of hCBMCs with IgE/antigen or LAD2 cells with SP leads to rapid (30 minutes) secretion of preformed TNF. Degranulation is accompanied by mitochondrial translocation from a perinuclear location to exocytosis sites. Extracellular calcium depletion prevents these effects, indicating calcium requirement. The calcium-dependent calcineurin and Drp1 are activated 30 minutes after SP stimulation. Reduction of Drp1 activity by mitochondrial division inhibitor and decrease of Drp1 expression using small interfering RNA inhibit mitochondrial translocation, degranulation, and TNF secretion. Mitochondrial translocation is also evident by transmission electron microscopy in skin mast cells from AD biopsies, in which gene expression of calcineurin, Drp1, and SP is higher than in normal skin. Human mast cell degranulation requires mitochondrial dynamics, also implicated in AD. (J Allergy Clin Immunol 2011;127:1522-31.)
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