新型抗炎细胞因子-IL-37在动脉粥样硬化中的作用和机制

Atherosclerosis is a multifactorial chronic inflammatory disease perpetuated by immune cells and its mediators, such as cytokines. Previous studies identified various pro-inflammatory cytokines as important regulators of atherosclerosis development. On the other hand, studies of negative regulators of inflammation such as anti-inflammatory cytokines are limited. IL-37 is a recently discovered fundamental inhibitor of immunity, yet its function in atherosclerosis remains unknown. Our recent data reveals IL-37 is decreased in patients with AS and IL-37 administration significantly decreases inflammation and atherosclerotic lesion development in ApoE-/- mice. On the basis of our findings, we hypothesize that IL-37 play important role in the regulatory network of inflammation in atherosclerosis. This proposal will extend our previous works to study the role of the newly found anti-inflammatory cytokine in the immune homeostasis regulation during atherosclerosis progression in the following specific aims. Specific Aim 1 will seek to understand whether IL-37 signaling pathway is down-regulated in ApoE-/- mice put on an atherogenic diet. Specific Aim 2 will examine the effect of IL-37 deficiency or overexpression on inflammation and atherosclerotic plaque formation. Specific Aim 3 will test the hypothesis that IL-37 play roles in differentiation of immune cells. Specific Aim 4 will dissect signaling pathways that orchestrate IL-37 dependent differentiation of immune cells. This study is expected to provide novel insights into the immune regulatory mechanisms of atherogenic responses. The findings may lead to new therapeutic approaches in prevention and treatment of atherosclerosis.

动脉粥样硬化（AS）是由炎性细胞和细胞因子等炎性介质持续作用引起的慢性炎症性疾病。现已发现多种促炎细胞因子可促进AS的发生发展，但至今对在AS中起负向调控作用的内源性抗炎性细胞因子仍知之甚少。IL-37是一种新型的免疫抑制因子，介导了多种炎症疾病的免疫再平衡。我们前期研究发现：IL-37在AS患者循环和不稳定斑块中的表达显著降低；IL-37可显著抑制小鼠血管炎症反应和AS斑块进展，提示IL-37可能参与了AS炎症反应和斑块进展的调控，但具体的作用和机制有待阐明。为此，本课题将通过观察AS进程中IL-37及其信号分子的表达规律；观察增强/阻断IL-37表达对AS炎症反应和斑块形成的影响；研究IL-37对不同炎性细胞分化的影响和信号分子机制，来验证IL-37是AS炎症反应和AS发生发展的重要内源性负向调节因子的假设。结果将有助于阐明AS发病机制，为构建血管免疫稳态再平衡，防治AS提供新的靶点。

本项目通过离体实验和在体实验，探讨了IL-37在动脉粥样硬化（AS）炎症反应中的调控作用和机制。结果发现：1.人的AS斑块中高度表达IL-37，与斑块炎症反应相关；2.IL-37可通过抑制巨噬细胞清道夫受体的表达抑制其泡沫化；3.IL-37转基因小鼠AS斑块面积明显减小；4.机制方面，IL-37通过树突状细胞受体IL-1R8，调节Th17/TH1/Treg失衡，抑制动脉粥样硬化炎症反应。上述结果充分证实了我们的假设，即：IL-37通过IL-1R8受体，抑制Smad3和TLR4/NFkb信号,导致抑炎细胞（Treg）活化/ 促炎细胞（TH1、TH17、DC）抑制，抑制AS。该结论为以IL-37为靶点，重建免疫稳态，防治动脉粥样硬化了提供理论基础，具有重要科学理论意义和临床指导意义。