IgE/FcεRI调控肥大细胞脱颗粒在颅内动脉瘤发病中的作用和机制

Intracranial aneurysms (IA) are common cerebrovascular disease, which poses grievousoutcomes in most cases. Despite of number studies concerning IA; the pathogenesis of this challenging lesions remains unclear. It has been postulated that chronic inflammation might be closely related to the formation of IA. Mast cell (MC) is considered as a key effector cell in the inflammation of the artery wall. Activated MC could degranulate and release a collection of pro-inflammatory cytokines, which are recognized as the promotor factors in the inflammation. Our previous research found that there were a large amount of MC degranulation in the human IA samples and the level of the inflammatory cytokines released by MC were significantly elevated；IA patients with elevated serum IgE and abnormal Fc receptor pathway activation. So we speculate that MC might have some implications in pathogenesis of IA. Based on this hypothesis, we established the IA mice model with the aid of stereotaxic injection. Then we make use of MC activation, MC inhibition, MC knock out and MC target-gene silence in IA mice model and the vitro cell co-culture system to study the influence of MC and its signal pathway in the pathogenesis of IA. Our study to investigate the role of MC in IA based on molecular research, animal model and clinical data might provide new insight for the treatment of IA in future.

颅内动脉瘤(IA) 是一种严重威胁人类生命健康的脑血管疾病。IA 发病机制尚未阐明，但近年研究提示IA 的发生与血管内炎症反应密切相关。肥大细胞（MC）是在血管炎症反应中至关重要的一类效应细胞。我们前期研究发现人IA 标本存在大量MC 脱颗粒现象，MC 释放炎症因子含量明显增高，患者血清IgE上升及Fc受体通路异常活化。我们推测MC可能参与IA 的形成。为证实这一假说，我们用MC敲除以及MC靶向基因敲除等转基因小鼠，通过疾病动物模型和细胞共培养体系，对MC上下游信号转导通路的靶向干扰，应用分子生物学、基因工程学、细胞生物学等方法，集中研究颅内动脉瘤发病过程中IgE如何介导肥大细胞脱颗粒而导致颅内动脉瘤的形成，并研究其通过何种信号转导途经完成此生物学事件。本研究将首次从人-动物模型-细胞-分子水平等多个层次来研究MC参与IA形成的机制，为IA的临床诊断治疗提供新思路和新靶点。

颅内动脉瘤是发生在颅内动脉管壁上的异常膨出，一旦破裂后将造成严重的脑出血而威胁人类生命健康。近年来大量的研究表明炎症细胞、炎症因子参与动脉血管的慢性炎症反应是导致颅内动脉瘤形成的关键因素。本实验通过检测颅内动脉瘤标本证实有大量炎症因子，如IgE, TNF-β1, IL-6等存在。这些炎症因子的存在可能与肥大细胞的激活和介质释放有关。进一步通过立体定向法构建颅内动脉瘤的动物模型，证实通过对肥大细胞的激活、抑制以及IgE与FcerI通路的活化，能够显著影响动脉瘤形成以及炎症因子的释放。通过IgE激活FcerI通路，促进肥大细胞脱颗粒可以显著促进颅内动脉瘤的形成；而阻断FcerI受体可以抑制颅内动脉瘤的形成。进一步深入研究后发现长链非编码RNA即LncRNA HIF1A-AS1，可能深度参与颅内动脉瘤的形成机制。血管平滑肌细胞破坏是颅内动脉瘤形成的基础病理生理过程。LncRNA HIF1A-AS1可能是通过诱导改变颅内动脉血管壁中TGF-β1的表达水平来从而来影响血管平滑肌细胞的增殖水平。肥大细胞与内皮细胞或者平滑肌细胞共培养，激活后可以显著促进其凋亡的出现。一旦血管平滑肌细胞大量死亡，颅内动脉瘤随着时间变化会破裂出血，导致大量的神经元细胞死亡、严重的神经功能障碍。