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的新机制途径一直是我整个研究生涯的主题。系统性红斑狼疮（SLE）是一种以致病性为特征的多器官和破坏性自身免疫性疾病。虽然人们已经认识到树突状细胞在疾病的发生中发挥着重要作用，但直到最近才有研究表明树突状细胞是该疾病的主要因素。 SLE 患者的 DC 表现出激活标记物的表达升高，包括共刺激分子和促炎细胞因子；然而，导致异常激活的因素尚不清楚，Caspase 8 是一种已知起作用的天冬氨酸酶。在死亡受体信号传导中，可以在多种细胞中启动细胞凋亡和/或抑制坏死性凋亡（通过抑制 RIPK1/3 信号传导）。初步研究表明，DC 中缺乏 caspase 8 的小鼠。 (CreCD11cCasp8flox/flox)，早在 2-3 个月大时，CreCD11cCasp8flox/flox 小鼠就表现出脾肿大、淋巴结肿大、dsDNA 反应性自身抗体、肾小球肾炎、肾脏中免疫复合物沉积、蛋白尿水平升高。血清促炎细胞因子（IL-12、IL-1¿ ，和干扰素¿ /¿ DC 中 caspase 8 的丢失不会影响其存活，但它们会被高度激活，从而以旁分泌方式导致活化淋巴细胞水平升高。与受体 7 和 9 (TLR7/9) 类似，因为 Caspase 8 缺陷的 DC 对 TLR7/9 连接表现出高反应性，且 DNA 增加此外，阻断 RIPK1 信号传导会抑制 Caspase 8 缺陷 DC 中 TLR7/9 诱导的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 信号传导至关重要。预防和/或限制 DC 的过度刺激和 SLE 样疾病的诱发 在整个五年计划中，我的进步和职业发展将由咨询委员会进行监测，其中包括我的导师和我的导师。其他四名成员，这个小组已经帮助我制定了我的研究计划，我的长期职业目标是建立一个学术研究小组，专注于了解风湿病发展背后的免疫机制，重点是系统性研究。我相信该提案是获得 K01 指导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，从而在该领域发展自己的利基市场。风湿病随着我开始建立独立的学术生涯。