RORγt调控IL-17相关炎性微环境对腹主动脉瘤作用机制研究

Abdominal aortic aneurysm (AAA) is a common and fatal vascular disease among the population in most countries. The chronic inflammatory responses play a key role in the progression of AAA. The microenvironment consisted of inflammatory cells and factors forms the basis for the persistent existence of chronic inflammation. Numerous studies show that IL-17 and its related immune cells are instrumental in the regulation of inflammatory microenvironment, and involved in many inflammatory diseases. However, the effect on AAA is still unclear. Our previous research work has indicated that antagonizing the activity of RORγt, the specific transcription factor of IL-17, confers protection against experimental abdominal aortic aneurysm via inhibiting the Th17/IL-17-related inflammatory responses. However, the deeper mechanism of RORγt in AAA lesions is still unknown, and further research work is needed. To fully explore the effect of RORγt in ILC3s (group3 innate lymphoid cells), γδT cells and traditional T lymphoid cells, the double gene knock-out mice, adoptive cell transfer, cell depletion with antibody and vitro cell experiments are used in this study. Moreover, this project will further elucidate the mechanism of RORγt in IL-17-related inflammatory microenvironment, and in the progression of AAA. This study may provide a novel strategy for non-surgical AAA treatment.

腹主动脉瘤是常见的高度致死性的大血管疾病。慢性炎症反应在腹主动脉瘤的发生发展中起重要作用。炎性细胞及细胞因子构成的微环境是慢性炎症持续存在的基础。研究表明IL-17及IL-17相关免疫细胞在炎性微环境的调控中发挥重要作用，参与多种炎性疾病发生发展，但其在腹主动脉瘤中的作用尚不明确。我们前期研究结果证实拮抗IL-17特异性转录因子RORγt活性可抑制Th17/IL-17反应，减缓小鼠实验性腹主动脉瘤的进展，但RORγt与腹主动脉瘤的深层次关系仍未得知，其机制有待进一步研究。本课题将利用基因敲除、细胞过继性输注、细胞抗体阻断等方案联合体外实验，探讨干预RORγt对固有淋巴细胞、γδT细胞、巨噬细胞及传统辅助T细胞的影响，明确其在炎症微环境中的调节机制和腹主动脉瘤中的作用机制，为腹主动脉瘤的临床治疗提供新的思路。

腹主动脉瘤是临床上常见的高致死性大血管疾病，尚无有效的治疗方法。以炎性细胞及细胞因子为核心的慢性炎症微环境是腹主动脉瘤发生发展的基础。研究表明IL-17及IL-17相关免疫细胞在炎性微环境的调控中发挥重要作用，参与多种炎性疾病发生发展，但其在腹主动脉瘤中的作用尚不明确。前期研究中我们发现在腹主动脉瘤患者组织标本中，JAK2、STAT3、IL-17A、VEGF在人腹主动脉瘤病变组织中高表达，同时血管壁周围有大量的炎性细胞（巨噬细胞）浸润。本研究通过构建AngII诱导的ApoE-/-小鼠实验性腹主动脉瘤模型，从体内和体外两方面研究，抑制IL-17A的表达，能显著的降低小鼠的成瘤率以及有效的保护腹主动脉管壁结构，减少炎性细胞和炎性因子的浸润。我们研究还发现JAK2/STAT3 信号通路在实验性腹主动脉瘤模型中的重要作用，并且IL-17可能通过JAK2/STAT3信号通路发挥作用。与此同时，通过干预炎症微环境中巨噬细胞M1/M2分化，调控巨噬细胞向抗炎型（M2）分化可延缓小鼠腹主动脉瘤的发生发展、降低血管壁炎性细胞浸润及相关炎症因子表达。调控炎性微环境中传统CD4+T细胞活化及抗原提呈细胞DC细胞也可以影响相关炎性因子表达、改善炎性微环境。该研究成果为腹主动脉瘤的临床治疗提供新的理论依据。