Early Life Stress Promotes an Inflammatory Phenotype Leading to Vascular Impairment and Lupus Nephritis Severity

项目摘要 暴露于早期生活压力（ELS）通常伴随着成年早期的不良健康结果， 具有更严重的程度，例如系统性红斑狼疮（SLE），一种自身免疫性疾病。的 自身免疫和心血管疾病（CVD）的风险随着ELS暴露而增加，CVD是ELS暴露的主要原因。 是SLE患者早期死亡的主要原因。这个项目解决了知识上的差距， 与ELS共存与SLE中较高的患病率和心脏病相关。在SLE的情况下- 尽管有报告将ELS患者的疾病活动性恶化联系起来，但尚未进行临床前研究。 SLE的啮齿动物模型与ELS联合。几项调查表明，ELS与 促炎表型和血管功能障碍。在我们的ELS小鼠模型中， 早期断奶（MSEW），我们观察到主动脉内皮功能障碍依赖于超氧化物和增加 主动脉外膜中F4/80+巨噬细胞（一种先天免疫细胞）的数量。此外，船 在经历降植烷诱导的SLE的MSEW小鼠中，功能障碍和主动脉僵硬被夸大。我们预计 血管功能损伤是由于MSEW动物中存在促炎性巨噬细胞。初步 数据显示线粒体功能障碍存在于MSEW小鼠中，表明超氧化物影响内皮细胞 功能障碍可能是线粒体衍生的。因此，我们的总体假设表明，ELS强调了 SLE小鼠模型中动脉疾病的发展和严重程度通过体内衍生的超氧化物 产生和激活的促炎巨噬细胞。该项目的设计有两个具体目标。第一、 我们将确定巨噬细胞是否介导ELS中主动脉疾病的发展。我们将使用流式细胞仪 和RNA测序以确定MSEW和对照小鼠之间的免疫活化差异。然后我们 将确定与对照相比，体内巨噬细胞的缺乏是否能预防MSEW血管功能障碍。 其次，研究将阐明ELS是否通过以下途径介导SLE主动脉疾病的发展增强： 线粒体超氧化物生成。降植烷诱导的SLE模型将与 MSEW方案，以确定是否氧化应激，以前与SLE介导的高血压，是加速 的ELS。实验将使用遥测技术和ELS后的血管反应性检查SLE中CVD的标志物。 我们还将测量通过MitoTEMPOL阻断线粒体超氧化物后的CVD和疾病。我们期望 见（i）炎性巨噬细胞升高，当缺乏时，减少血管功能障碍和（ii）更大的CVD MSEW SLE小鼠中的负荷通过MitoTEMPOL治疗降低。这个项目对于开始理解 ELS在SLE中的机制关系以及对研究免疫驱动疾病与CVD的关键 并发症ELS与多种疾病的不良健康结果相关。ELS的进展 这些领域对于为患者制定相关和可获得的干预和预防战略至关重要。我们 研究为ELS驱动的CVD提供了两种潜在的互补途径。

PROJECT SUMMARY Exposure to early life stress (ELS) often is accompanied by adverse health outcomes earlier in adulthood and with more severity such as in the case of Systemic Lupus Erythamateous (SLE), an autoimmune disease. The risk for autoimmunity and cardiovascular disease (CVD) increases with ELS exposure and CVD is the predominant cause for early mortality in SLE patients. This project addresses the gap in knowledge of why coexistence with ELS is associated with higher prevalence and heart disease in SLE. In the case of SLE— despite reports linking worsened disease activity in patients with ELS—there have been no studies in preclinical rodent models of SLE in conjunction with ELS. Several investigations demonstrate that ELS is associated with a pro-inflammatory phenotype and vascular dysfunction. In our mouse model of ELS, maternal separation with early weaning (MSEW), we observed aortic endothelial dysfunction dependent on superoxide and increased numbers of F4/80+ macrophages, an innate immune cell, in the adventitia of the aorta. In addition, vessel dysfunction and aortic stiffness is exaggerated in MSEW mice subjected to pristane induction of SLE. We expect impairment in vascular function is due to proinflammatory macrophage presence in MSEW animals. Preliminary data shows mitochondrial dysfunction is present in MSEW mice indicating the superoxide impacting endothelial dysfunction may be mitochondrial derived. Thus, our overall hypothesis states that ELS accentuates the development and severity of aortic disease in a mouse model of SLE through mitochondrial-derived superoxide production and activated pro-inflammatory macrophages. This project is designed with two specific aims. First, we will determine if macrophages mediate development of aortic disease in ELS. We will use flow cytometry and RNA sequencing to determine immune activation differences between MSEW and control mice. We then will determine if absence of macrophages in vivo prevents MSEW vascular dysfunction compared to controls. Second, studies will address if ELS mediates enhanced development of aortic disease in SLE through mitochondrial superoxide production. The pristane-induced model of SLE will be used in conjunction with the MSEW protocol to determine if oxidative stress, previously linked to SLE-mediated hypertension, is accelerated by ELS. Experiments will examine markers for CVD in SLE using telemetry and vascular reactivity after ELS. We will also measure CVD and disease after blocking mitochondrial superoxide by MitoTEMPOL. We expect to see (i)elevated inflammatory macrophages that, when absent, reduce vascular dysfunction and (ii)a greater CVD burden in MSEW SLE mice reduced by MitoTEMPOL treatment. This project is critical to begin to understand the mechanistic relationship of ELS in SLE as well as crucial for studying immune driven diseases with CVD complications. ELS is associated with adverse health outcomes in a variety of diseases. Advances in the ELS field are essential to developing relevant and accessible intervention and prevention strategies for patients. Our studies provide two potentially complementary pathways for ELS-driven CVD.