Metabolic Consequences of IgE- and Non-IgE-Mediated Mast Cell Degranulation.
Metabolic Consequences of IgE- and Non-IgE-Mediated Mast Cell Degranulation.
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DOI：
10.4049/jimmunol.2001278
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Brown JM
中科院分区：
文献类型：
--
作者：
Mendoza RP;Anderson CC;Fudge DH;Roede JR;Brown JM
肥大细胞是免疫系统中重要的效应细胞，通过两种主要机制激活(即脱颗粒)：IgE介导和非IgE介导。虽然IgE介导的脱颗粒已经被很好地研究了，但非IgE介导的肥大细胞激活的细胞机制却知之甚少，尽管可能会引起类似的病理生理效应。为了更好地了解非IgE肥大细胞脱颗粒，我们对小鼠骨髓来源的肥大细胞(BMMCs)中几种脱颗粒机制(变应原诱导的[IgE介导的]、20 nm纳米银颗粒介导的[非IgE]和化合物48/80介导的[非IgE])的代谢变化进行了表征和比较。所有处理都不同地影响线粒体活性和葡萄糖摄取，表明IgE和非IgE介导的脱颗粒之间的代谢途径不同。非IgE处理耗尽了肥大细胞的糖酵解储备，化合物48/80进一步抑制了最大化线粒体呼吸的能力。这种细胞重编程可能预示着非IgE治疗的应激反应。这两种结果都不会发生在IgE介导的脱颗粒中，这暗示了单独的程序性反应。在激活的细胞中，三种主要线粒体营养来源之间的燃料灵活性也被消除，这在非IgE介导的脱颗粒中最为显着。最后，对脱颗粒后的BMMCs进行代谢组学分析，以比较与能量途径相关的一般代谢物谱。与其他治疗方法相比，免疫球蛋白介导的脱颗粒可上调TCA循环和糖酵解的代谢物浓度。综上所述，在IgE和非IgE介导的脱颗粒中，肥大细胞的代谢显著不同，提示新的细胞调节机制潜在地驱动了肥大细胞脱颗粒的未知途径。
Mast cells are important effector cells in the immune system and undergo activation (i.e. degranulation) by two major mechanisms: IgE mediated and non-IgE mediated. While IgE mediated degranulation is well researched, the cellular mechanisms of non-IgE mediated mast cell activation are poorly understood despite the potential to induce similar pathophysiological effects. To better understand non-IgE mast cell degranulation, we characterized and compared cellular metabolic shifts across several mechanisms of degranulation (allergen-induced [IgE mediated], 20 nm silver nanoparticle mediated [non-IgE], and compound 48/80 mediated [non-IgE]) in murine bone marrow-derived mast cells (BMMCs). All treatments differentially impacted mitochondrial activity and glucose uptake, suggesting diverging metabolic pathways between IgE and non-IgE mediated degranulation. Non-IgE treatments depleted mast cells’ glycolytic reserve and compound 48/80 further inhibited the ability to maximize mitochondrial respiration. This cellular reprogramming may be indicative of a stress response with non-IgE treatments. Neither of these outcomes occurred with IgE mediated degranulation, hinting at a separate programmed response. Fuel flexibility between the three primary mitochondrial nutrient sources was also eliminated in activated cells and this was most significant in non-IgE mediated degranulation. Lastly, metabolomics analysis of BMMCs following degranulation was used to compare general metabolite profiles related to energetic pathways. IgE mediated degranulation upregulated metabolite concentrations for the TCA cycle and glycolysis compared to other treatments. In conclusion, mast cell metabolism varies significantly between IgE and non-IgE mediated degranulation suggesting novel cell regulatory mechanisms are potentially driving unexplored pathways of mast cell degranulation.
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