HMGB2-Trem途经失调促进腹主动脉瘤发生的机制研究

Immunity plays a role in the development of abdominal aortic aneurysm (AAA). We obtained samples of AAA and aortic control tissues, and performed mRNA chips. By comparing with controls, the expression of Trem-1, a member of triggering receptor expressed on myeloid cells (TREM) family, and its ligand HMGB2 increased significantly. In contrast, the expression of Trem-2 decreased greatly. Consistent changes were observed in CaCl2-induced mouse models with AAA. In vitro, HMGB2 caused an enhancement of inflammatory cytokine and matrix metalloproteinase production and TLR4 & RAGE expression in macrophages, and induced a pro-inflammatory M1 polarization. Similar phenomenon revealed in vascular smooth muscle cells while stimulating with HMGB2. Such effects were however significantly antagonized by Trem-1 siRNA and overexpression of Trem-2 in both macrophages and vascular smooth muscle cells. Trem-2 exhibited anti-inflammatory influences. Collectively, these results have suggested that the disturbance of HMGB2-Trem might be closely involved in the development of AAA. In our next researches, we will test our hypothesis by establishing AAA models using wide-type, Trem-1-KO, and Trem-2-KI mice. The mechanism will be investigated in animal models and in cell experiments using mouse-derived macrophages and vascular smooth cells. Aortic tissue samples and plasma from patients with AAA will be used to confirm our hypothesis.

腹主动脉瘤（AAA）发病与免疫异常有关。我们运用mRNA芯片检测并分析发现，AAA组织较对照组织中固有免疫受体Trem-1及其配体HMGB2显著增高，而Trem-2降低。在CaCl2诱导的小鼠AAA模型中病变动脉也表现类似。在巨噬细胞中，HMGB2经Trem-1介导促进炎性因子和金属蛋白酶表达；诱导巨噬细胞向促炎性M1极化；还上调固有免疫受体TLR4和RAGE表达。平滑肌细胞中也有类似现象。但这些促进AAA发生的效应能被siRNA下调Trem-1或Trem-2过表达所拮抗，且Trem-2显示抗炎特性。结合文献提示，HMGB2-Trem途径失调促进AAA发生。后续将运用野生型、Trem-1-KO和Trem-2-KI小鼠制作AAA模型；以细胞株、小鼠巨噬细胞和动脉平滑肌细胞等行体外实验，腺病毒过表达HMGB2等手段，并用AAA患者样本验证假说，阐明HMGB2-Trem途径失调促进AAA的机制。

背景和目的：腹主动脉瘤隐匿性强，早发现率低，大部分患者在 AAA 破裂之前没有任何先兆，一旦破裂死亡率极高，深入了解AAA的发病机制对于开发有效的药物治疗来阻止腹主动脉瘤形成和防止破裂是必要的。本研究的目的是阐明高迁移率族蛋白B（HMGB）对AAA发生发展的影响。.材料和方法：使用野生型小鼠和HMGB2-/-小鼠建立CaCl2诱导的AAA模型，以评估HMGB2在AAA发生发展过程中的作用。（1）进行免疫荧光和流式细胞术以分析巨噬细胞极化。（2）我们通过小鼠骨髓衍生的巨噬细胞（BMDM）进行体外研究，以确定HMGB2的下游信号通路。（3）测量AAA患者的血清HMGB2水平，进一步分析其与最大主动脉直径的相关性。.结果：CaCl2诱导的AAA小鼠血浆和主动脉组织中HMGB2的表达增加，HMGB2-/-小鼠的AAA进展受到抑制。HMGB2敲除后，AAA组织内M1巨噬细胞减少。机制上，细胞外HMGB2与巨噬细胞表面的TREM-1结合，并引发促炎细胞因子的分泌，如白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α和单核细胞趋化蛋白（MCP）-1。此外，AAA患者血清HMGB2水平升高，与AAA严重程度呈正相关。.结论：这些发现表明，细胞外HMGB2是AAA加重的因子，其通过与TREM-1结合并促进M1巨噬细胞极化而起作用。