Caspase 8: A Novel Suppressor of Dendritic Cell-Mediated Autoimmunity

Caspase 8：树突状细胞介导的自身免疫的新型抑制剂

• 批准号: 8487862
• 负责人: Carla M Cuda
• 金额: $ 11.93万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487862
• 关键词: Activated Lymphocyte; Adverse effects; Advisory Committees; Affect; Age-Months; Agonist; Apoptosis; Aspartic Acid; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Belief; Caspase Inhibitor; Cell Survival; Cells; Cellular biology; Cessation of life; Cysteine; DNA Binding; Data; Dendritic Cells; Dendritic cell activation; Deposition; Development; Disease; Disease remission; Enzymes; Exhibits; Focus Groups; Genetic Polymorphism; Genetic Transcription; Goals; Immune; Immune Complex Glomerulonephritis; Immunologics; Inflammation; Inflammatory; Interferons; Interleukin-12; Kidney; Lead; Ligation; Lymphatic Diseases; Lymphoid Cell; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Monitor; Mus; Myeloid Cells; Necrosis; Nucleic Acids; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Predisposition; Process; Production; Proteinuria; RIPK1 gene; RIPK3 gene; Receptor Signaling; Relapse; Research; Research Proposals; Rheumatism; Role; Serum; Signal Transduction; Splenomegaly; Systemic Lupus Erythematosus; Therapeutic immunosuppression; Training; career; caspase-8; cytokine; effective therapy; functional loss; genetic variant; human TLR7 protein; inhibitor/antagonist; member; mortality; novel; overexpression; paracrine; prevent; programs; public health relevance; response

DESCRIPTION (provided by applicant): Uncovering novel mechanistic pathways involved in immune cell-mediated pathogenesis of autoimmune rheumatic diseases has been a consistent theme throughout my research career. Systemic lupus erythematosus (SLE) is a multi-organ and destructive autoimmune disease characterized by pathogenic autoantibodies. While it has been accepted that dendritic cells play an important role in the initiation of the disease, only recently have studies now implicated DCs as a major factor in the persistence of SLE. DCs from patients with SLE exhibit elevated expression of activation markers including co-stimulatory molecules and pro- inflammatory cytokines; however, the factors that are responsible for the aberrant activation is unknown. Caspase 8, an aspartic enzyme known to function in death receptor signaling, can initiate apoptosis and/or suppress necroptosis (through inhibition of RIPK1/3 signaling) in a multitude of cells. Preliminary studies show that mice lacking caspase 8 in DCs (CreCD11cCasp8flox/flox), exhibit a break in tolerance at as early as 2-3 months of age. CreCD11cCasp8flox/flox mice display splenomegaly, lymphadenopathy, dsDNA-reactive autoantibodies, glomerulonephritis, immune complex deposition in the kidney, exacerbated proteinuria levels, heightened amounts of serum pro-inflammatory cytokines (IL-12, IL-1¿, and IFN¿/¿)and early mortality. Loss of caspase 8 in DCs does not affect their survival, but they are highly activated, leading to elevated levels of activated lymphocytes in a paracrine manner. The increased activation potential of CreCD11cCasp8flox/flox DCs may be controlled by toll-like receptos 7 and 9 (TLR7/9) since caspase 8-deficient DCs display a hyper- responsiveness to TLR7/9 ligation with increased DNA binding activity of interferon regulatory factor (IRF). Additionally, blocking RIPK1 signaling dampens the TLR7/9-induced secretion of pro-inflammatory cytokines in caspase 8-deficient DCs. Collectively, these data suggest that intact caspase 8 signaling in DCs is crucial for preventing and/or limiting the hyper stimulation of DCs and induction of SLE-like disease. My progress and career advancement will be monitored throughout the five-year program by an Advisory Committee, which will include my mentor and four other members, and this group has already been instrumental in helping me develop my research proposal. My long-term career goal has been to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic diseases, with an emphasis on systemic lupus erythematosus (SLE). It is my belief that this proposal is an ideal training vehicle for a K01 Mentored Research Scientist Development Award, as I will become proficient in DC biology, as well as signal transduction, thereby developing my own niche in rheumatic disease as I begin to establish an independent academic career.

描述(由申请人提供)：揭示免疫细胞介导的自身免疫性风湿病发病机制是我整个研究生涯中一贯的主题。系统性红斑狼疮(SLE)是一种以致病性自身抗体为特征的多器官、破坏性自身免疫性疾病。虽然树突状细胞在SLE的发病中起着重要作用，但直到最近才有研究表明，树突状细胞是SLE持续存在的主要因素。SLE患者DC的激活标志物包括共刺激分子和促炎细胞因子的表达升高，但导致异常激活的因素尚不清楚。Caspase 8是一种天冬氨酸酶，在死亡受体信号转导中发挥作用，可以启动多种细胞的凋亡和/或抑制坏死性下垂(通过抑制RIPK1/3信号)。初步研究表明，在树突状细胞中缺乏caspase 8的小鼠(CreCD11cCasp8flx/flx)，在2-3个月大的时候就表现出耐受性的破坏。CreCD11cCasp8FLOX/FLOX小鼠表现为脾肿大、淋巴结肿大、dsDNA反应性自身抗体、肾小球肾炎、肾脏免疫复合物沉积、蛋白尿水平加重、血清促炎细胞因子(IL-12、IL-1β和干扰素/α)水平升高以及早期死亡。Caspase8的缺失不会影响DC的存活，但它们被高度激活，导致旁分泌方式激活的淋巴细胞水平升高。由于Caspase 8缺陷的DC对TLR7/9的DNA结合活性增加，Caspase8缺陷的DC对TLR7/9的高反应性，其激活潜能的增加可能受Toll样受体7和9(TLR7/9)控制。此外，阻断RIPK1信号可抑制TLR7/9诱导的Caspase 8缺陷DC促炎细胞因子的分泌。综上所述，这些数据表明，DC中完整的caspase 8信号对于防止和/或限制DC的过度刺激和诱导SLE样疾病至关重要。在整个五年计划中，我的进步和职业发展将由一个咨询委员会监督，该委员会将包括我的导师和其他四名成员，这个委员会已经帮助我制定了研究方案。我的长期职业目标是建立一个学术研究小组，专注于了解风湿性疾病发生的免疫学机制，重点是系统性红斑狼疮(SLE)。我相信，这项提议是K01导师研究科学家发展奖的理想培训工具，因为我将精通DC生物学以及信号转导，从而在我开始建立独立的学术生涯时，在风湿病领域开拓自己的利基市场。