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首页> 外文期刊>Allergy >The orphan nuclear receptor NR4A1 promotes Fc epsilon RI-stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis
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The orphan nuclear receptor NR4A1 promotes Fc epsilon RI-stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

机译：孤儿核受体NR4A1通过抵消抑制性LKB1 / AMPK轴来促进Fcε1i刺激的肥大酱细胞活化和过敏反应

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Background Nuclear receptor subfamily 4 group A member 1 (NR4A1), an orphan nuclear receptor, has been implicated in several biological events such as metabolism, apoptosis, and inflammation. Recent studies indicate a potential role for NR4A1 in mast cells, yet its role in allergic responses remains largely unknown. Objectives The aim of this study was to clarify the role of NR4A1 in mast cell activation and anaphylaxis. Methods To evaluate the function of NR4A1 in mast cells, the impacts of siRNA knockdown, gene knockout, adenoviral overexpression, and pharmacological inhibition of NR4A1 on Fc epsilon RI signaling and effector functions in mouse bone marrow-derived mast cells (BMMCs) in vitro and on anaphylactic responses in vivo were evaluated. Results Knockdown or knockout of NR4A1 markedly suppressed degranulation and lipid mediator production by Fc epsilon RI-crosslinked BMMCs, while its overexpression augmented these responses. Treatment with a NR4A1 antagonist also blocked mast cell activation to a similar extent as NR4A1 knockdown or knockout. Moreover, mast cell-specific NR4A1-deficient mice displayed dampened anaphylactic responses in vivo. Mechanistically, NR4A1 promoted Fc epsilon RI signaling by counteracting the liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) axis. Following Fc epsilon RI crosslinking, NR4A1 bound to the LKB1/AMPK complex and sequestered it in the nucleus, thereby promoting Fc epsilon RI downstream signaling pathways. Silencing or knockout of LKB1/AMPK largely abrogated the effect of NR4A1 on mast cell activation. Additionally, NR4A1 facilitated spleen tyrosine kinase activation independently of LKB1/AMPK. Conclusions Nuclear receptor subfamily 4 group A member 1 positively regulates mast cell activation by antagonizing the LKB1-AMPK-dependent negative regulatory axis. This finding may provide a novel therapeutic strategy for the development of anti-allergic compounds.
机译：背景技术核受体亚家族4组构件1（NR4A1），孤儿核受体，含有若干生物事件，例如代谢，细胞凋亡和炎症。最近的研究表明NR4A1在肥大细胞中的潜在作用，但其在过敏反应中的作用仍然很大程度上是未知的。目的本研究的目的是阐明NR4A1在肥大细胞活化和过敏反应中的作用。评价肥大细胞中NR4A1功能的方法，siRNA敲低，基因敲除，腺病毒过度表达的影响，NR4a1对小鼠骨髓型肥大细胞（BMMC）的FC EPSILON RI信号传导和效应功能的影响评价体内过敏反应的研究。结果NR4A1的敲低或敲除通过FCε中交联BMMC显着抑制了脱粒和脂质介质生产，而其过度表达增强了这些反应。用NR4A1拮抗剂治疗也将肥大细胞活化置于与NR4A1敲低或敲除类似的程度。此外，肥大细胞特异性NR4A1缺陷小鼠在体内显示抑制过敏性反应。机械地，NR4A1通过抵消肝激酶B1（LKB1）/腺苷活化的蛋白激酶（AMPK）轴来促进FCε1的信号传导。在FCε11交联之后，NR4A1与LKB1 / AMPK复合物结合并在核中隔离，从而促进FCεRI下游信号通路。 LKB1 / AMPK的沉默或敲除大部分废除了NR4A1对肥大细胞活化的影响。另外，NR4A1促进了脾脏酪氨酸激酶活化，独立于LKB1 / AMPK。结论核受体亚家族4组通过拮抗LKB1-AMPK依赖性的阴性调节轴来阳性调节肥大细胞活化。该发现可以为抗过敏化合物的发展提供新的治疗策略。

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