新型细胞因子IL-36γ在动脉粥样硬化过程中的功能及分子机制研究

Atherosclerosis is a chornic inflammatory disease characterized by the accumulation of lipids and fibrous elements in the large arteries. Over time, these lesions, which are known as atherosclerotic plaques, mature and gain new characteristics. In atherosclerosis, the key initiating step is that the subendothelial accumulation of apolipoprotein B-containing lipoproteins leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages. Macrophages derived from these recruited monocytes ingest the accumulated normal and modified lipoproteins, which transform them into the cholesterol-laden foam cells, triggering a series of inflammatory response. Macrophage-derived foam cell formation is a critical early event in atherogenesis, with an incomplete understanding of the molecular pathways involved. IL-36γ (formerly known as IL-1F9) is novel IL-1 cytokine family member, which recruits the IL-1R accessory protein after binding specifically to the IL-36 receptor and leads to the activation of NF-kB and MAPK pathways. Recent studies showed that IL-36 cytokines play an important role in the pathogenesis of rheumatoid arthritis, psoriasis, gut inflammation or pulmonary disease. However, there are few reports regarding the function of IL-36 in atherosclerosis. Our recent results found that IL-36γ promoted atherosclerosis in an ApoE–/–mouse model and IL-36γ was a novel regulator of macrophage foam cell formation and macrophage recruitment. In this study, we will explore the function and molecular mechanism of IL-36γ in the development of atherosclerosis in cultured cells, animal models and clinical cases. Therapeutic approaches that target macrophages to treat cardiovascular disease have not yet been realized, partly because the fundamental biology remains somewhat enigmatic. Our study provides a new insight to macrophage function and regulation in atherosclerosis as well as the novel role of IL-36γ in the development of cardiovascular disease.

动脉粥样硬化是一种危害极大的慢性炎症过程，主要特征是在动脉血管壁内形成富含脂质的斑块导致血管管腔狭窄，引起心脏和脑部缺血。在动脉粥样硬化的自然病程中，巨噬细胞来源的泡沫细胞的形成过程非常关键，其相关的调控分子及分子机制是动脉粥样硬化研究领域的热点问题。IL-36γ是近期发现的与IL-1结构相似的新型细胞因子簇成员，可以诱导促炎因子的表达，但在心血管疾病病理生理过程中的功能尚不清楚。我们近期利用小鼠模型的研究发现，IL-36γ可以促进动脉粥样硬化的发展，并可以调控小鼠骨髓来源巨噬细胞的募集和泡沫细胞的形成。在此基础上，本项目拟从临床样本、动物模型、细胞水平、分子水平等多个层面，系统研究IL-36γ在动脉粥样硬化疾病发生发展过程中的可能功能及分子机制。研究结果将首次为认识新型细胞因子IL-36γ在心血管疾病的重要调控作用提供科学依据，为动脉粥样硬化的临床治疗提供新思路。

动脉粥样硬化是一种危害极大的慢性炎症过程，主要特征是在动脉血管壁内形成富含脂质的斑块导致血管管腔狭窄，引起心脏和脑部缺血。在动脉粥样硬化的自然病程中，巨噬细胞来源的泡沫细胞的形成过程非常关键，其相关的调控分子及分子机制是动脉粥样硬化研究领域的热点问题。IL-36γ是近期发现的与IL-1结构相似的新型细胞因子簇成员，可以诱导促炎因子的表达，但在心血管疾病病理生理过程中的功能尚不清楚。本项目从动物模型、细胞水平、分子水平等多个层面，系统研究了IL-36γ在动脉粥样硬化疾病发生发展过程中的功能及分子机制。研究首先发现IL-36γ可以促进动脉粥样硬化的发展，并可以调控小鼠骨髓来源巨噬细胞的泡沫细胞形成，进一步研究发现IL-36γ促进巨噬细胞对氧化低密度脂蛋白的摄取。结合生物信息学分析和体内外生化实验，发现IL-36γ特异性上调脂蛋白摄取过程中关键的清道夫受体CD36的表达。机制研究表明，IL-36γ通过PI3K信号通路调控CD36的转录过程。该研究发现了新型细胞因子IL-36γ在心血管疾病的重要调控作用提供科学依据，为动脉粥样硬化的临床治疗提供新思路。