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

项目总结 暴露于早期生活压力(ELS)通常伴随着成年早期和成年后的不良健康后果 病情更为严重，如系统性红斑狼疮(SLE)，这是一种自身免疫性疾病。这个 自身免疫和心血管疾病(CVD)的风险随着ELS暴露而增加，CVD是 SLE患者早期死亡的主要原因。这个项目解决了人们对为什么 SLE合并ELS与较高的患病率和心脏病相关。就系统性红斑狼疮而言- 尽管有报道表明ELS患者的疾病活动恶化--但还没有临床前研究 系统性红斑狼疮合并ELS的啮齿动物模型。多项调查表明ELS与 一种促炎表型和血管功能障碍。在我们的ELS小鼠模型中，母体分离 早期断奶(MSEW)，我们观察到依赖于超氧化物的主动脉内皮功能障碍并增加 F4/80+巨噬细胞是一种先天免疫细胞，位于主动脉外膜。此外，船舶 在普瑞斯坦诱导的系统性红斑狼疮的MSEW小鼠中，功能障碍和主动脉僵硬被夸大。我们预计 血管功能受损是由于MSEW动物中存在促炎巨噬细胞所致。初步 数据显示，MSEW小鼠存在线粒体功能障碍，表明超氧化物影响内皮细胞 功能障碍可能源于线粒体。因此，我们的总体假设是ELS强调了 线粒体源性超氧化物歧化在系统性红斑狼疮小鼠模型中主动脉病变的发生和严重程度 产生和激活促炎巨噬细胞。这个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参与ELS中主动脉疾病的发生。我们将使用流式细胞术 和RNA测序，以确定MSEW和对照小鼠之间的免疫激活差异。然后我们 将确定与对照组相比，体内巨噬细胞的缺失是否可以防止MSEW血管功能障碍。 其次，研究将探讨ELS是否通过以下途径促进SLE患者主动脉病变的发展 线粒体超氧化物的产生。Pristane诱导的SLE模型将与 MSEW方案确定氧化应激是否加速，以前与SLE介导性高血压有关 被ELS。实验将使用遥测和ELS后的血管反应性来检查SLE中CVD的标志物。 我们还将测量血管密度和用MitoTEMPOL阻断线粒体超氧化物歧化后的疾病。我们希望 见(I)炎性巨噬细胞增多，当没有炎性巨噬细胞时，可减少血管功能障碍和(Ii)更大的心血管疾病 米托替普治疗减轻MSEW狼疮小鼠的负担。这个项目对于开始理解 系统性红斑狼疮中ELS的机制关系及其对研究免疫诱导性疾病与心血管疾病的关系 并发症。ELS与多种疾病的不良健康结局有关。ELS的研究进展 实地是为患者制定相关和可获得的干预和预防战略所必需的。我们的 研究为ELS驱动的心血管疾病提供了两条潜在的互补途径。

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.