IL-17通过NF-κB/IRF-1/SOCS1通路与IFN-γ相拮抗对SLE早发AS发挥保护作用

The key pathogenic roles of Th17 cells and their main effector-interleukin-17 (IL-17) in development of autoimmune diseases have been confirmed. Blockage of IL-17 has been expected to be one of the most important treatments for patients with systemic lupus erythematosus (SLE). The patients with SLE have higher risk and more serious lesions of cardiovascular diseases, including atherosclerosis(AS), but the influence of increased expression of IL-17 in patients with SLE on the development of AS is still obscure. It has been reported that IL-17 could play protective roles on cardiovascular diseases by inhibiting progression of AS, but the underlying mechanisms need to be further addressed. Our preliminary data indicates that IL-17 shows an anti-atherosclerotic action by obviously reversing atherogenic effects of interferon-γ(IFN-γ)in macrophages possibly by increasing expression of suppressor of cytokine signaling1(SOCS1). In this study, we will detect the antagonistic effects and its underlying molecular mechanisms of IL-17 on IFN-γ in macrophages through NF-κB/IRF-1/SOCS1 pathways. We will also observe the influences of interaction between IFN-γ and IL-17 on the development of AS in SLE using ApoE-/-lpr-/- mice. In addtion, we will intensively investigate the possible approach and its underlying mechanisms about antagonistic effects of Th17/IL-17 system on the development of AS. Our study may offer new thought on clinical treatment and resonable administration for the patients with SLE.

SLE患者具有包括AS在内的心血管系统疾病发病风险高、病变程度重的特点。疾病进程中表达增加的IL-17虽有望成为SLE等自身免疫性疾病干预和治疗的新靶点，但其对早发AS病变的影响尚不清楚。有报道显示，IL-17可以抑制普通AS的进程并具有一定的心血管保护作用，但机理不清。我们前期研究结果提示，在巨噬细胞内，IL-17可以通过显著拮抗IFN-γ的相关效应而发挥AS保护作用，这一作用可能与其增加SOCS1的表达有关。本课题拟以巨噬细胞为切入点，深入探讨IL-17通过NF-κB/IRF-1/SOCS1通路拮抗IFN-γ作用的细胞分子机理；并通过ApoE-/-lpr-/-双敲小鼠的应用，进一步探究IL-17与IFN-γ间的相互作用在SLE早发AS病变进程中的作用，为深入理解Th17/IL-17系统抗AS进程的可能途径及其分子机制提供新的思路，也为SLE早发AS的临床防治及合理用药提供实验依据。

系统性红斑狼疮(Systemic lupus erythematosus, SLE)患者动脉粥样硬化(Atherosclerosis, AS)等心血管系统疾病的发病风险高、病变程度重。疾病进程中表达增加的白介素-17（Interleukin-17, IL-17）对该类患者AS病变的影响尚不清楚。有报道显示，IL-17可以抑制普通AS的进程并具有一定心血管保护作用，但机理尚不清楚。结合前期预实验结果，我们提出IL-17可能通过对经典促AS因子干扰素-γ(Interferon-γ, IFN-γ)相关效应的拮抗而发挥AS保护作用。本研究通过体内、外实验探讨IL-17对IFN-γ引发的巨噬细胞促AS效应的影响和机制，以及IL-17阻断对SLE早发AS斑块病变进程的影响。结果发现：IFN-γ可以增加巨噬细胞ox-LDL的蓄积，减少胆固醇逆向转运蛋白ABCA1、ABCG1以及核受体LXR-α的表达，同时增加炎症因子ICAM-1、TNF-α以及MCP-1的表达。IL-17与IFN-γ联合应用可明显拮抗IFN-γ的作用，部分逆转IFN-γ引起的细胞脂质蓄积及炎症反应的活化；IL-17与IFN-γ可通过NF-κB和p-STAT1信号通路协同增加巨噬细胞IRF-1的转录及表达，并进一步通过大幅增加SOCS1的表达对IFN-γ的促AS效应产生拮抗；ApoE-/-lpr-/-小鼠血浆中IL-17、IFN-γ、TNF-α、MCP-1等细胞因子的含量显著升高。与ApoE-/-lpr+/+对照组小鼠相比，其主动脉根部出现了更为明显的粥样斑块，斑块面积较大。斑块内炎细胞的浸润也更为明显。采用中和抗体对IL-17的作用进行阻断，ApoE-/-lpr-/-小鼠主动脉根部粥样斑块及坏死核心的面积进一步增大，斑块内的脂质聚集更为明显，而胶原纤维的沉积有所减少，说明斑块的稳定性降低、易损性增加。这些结果提示，IL-17可以通过巨噬细胞NF-κB/IRF-1/SOCS1信号通路抑制小鼠SLE早发AS病变的发展进程。因此，Th17通路阻断类药物对SLE患者AS病变的进程及该类患者心血管不良事件的发生可能具有潜在不良影响，其在临床工作中的应用尚需进一步的评估和监测。