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（由适用提供）：揭示与免疫细胞介导的自身免疫性风湿病发病机理有关的新型机械途径一直是我整个研究职业的一致主题。全身性红斑狼疮（SLE）是一种多器官和破坏性的自身免疫性疾病，其特征是致病性自身抗体。尽管已经接受树突状细胞在疾病的开始中起着重要作用，但直到最近才实施DC作为SLE持续性的主要因素。来自SLE患者的DC表现出升高的激活标记表达升高，包括共刺激分子和促炎性细胞因子；但是，导致异常激活的因素尚不清楚。 caspase 8是一种已知在死亡受体信号传导中起作用的天冬氨酸酶，可以引发凋亡和/或抑制多种细胞中的RIPK1/3信号传导（通过抑制RIPK1/3信号传导）。初步研究表明，在DCS（CRECD11CCASP8FLOX/FLOX）中缺少caspase 8的小鼠早在2-3个月大时就会出现耐受性的突破。 CRECD11CCASP8FLOX /FLOX小鼠表现出脾肿大，淋巴结病，DsDNA反应性自身抗体，肾小球肾上腺炎，肾脏中免疫复杂沉积，加剧蛋白尿水平，血清血清促炎的含量较高，并提高了摄入症的终结（IL-12，IL-1-和IL-1。 DC中caspase 8的损失不会影响其存活，但被高度激活，导致旁分泌的活化淋巴细胞水平升高。 CRECD11CCASP8FLOX/FLOX DC的激活潜力可以通过Toll样受体7和9（TLR7/9）来控制，因为Caspase 8缺陷DCS表现出对TLR7/9的过度反应性，其结合具有增加的DNA结合活性（IRF）的DNA结合活性（IRF）。此外，阻断RIPK1信号传导会抑制TLR7/9诱导的caspase 8缺陷DC中促炎细胞因子的分泌。总的来说，这些数据表明，DC中完整的caspase 8信号传导对于防止和/或限制DC的过度刺激和诱导SLE样疾病至关重要。我的进步和职业发展将在整个五年计划中得到一个咨询委员会的监控，我相信这项建议是K01指导研究科学家发展奖的理想训练工具，因为我将精通DC生物学以及信号转导，因此随着我开始建立独立的学术生涯，我开始在风湿病中发展自己的Niche。