Characterization of a novel C1q-dependent engulfment pathway in autoimmunity

自身免疫中新型 C1q 依赖性吞噬途径的表征

• 批准号: 8693206
• 负责人: Suzanne Slater Bohlson
• 金额: $ 25.65万
• 依托单位: DES MOINES UNIV OSTEOPATHIC MEDICAL CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693206
• 关键词: Affect; American; Antigen-Antibody Complex; Apoptotic; Attention; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Binding; Cell surface; Cells; Chronic; Chronic Disease; Classical Complement Pathway; Collectins; Collection; Complement; Complement 1q; Data; Defect; Deposition; Development; Diagnostic; Disease; Etiology; Failure; Family; Gene Expression; Generations; Goals; Grant; Growth; Homologous Gene; Human; Immune response; In Vitro; Inflammation; Inflammatory; Kidney; Knockout Mice; Ku70 protein; Life; Ligands; Lupus; Mediating; Metabolism; Molecular; Molecular Target; Mus; Nuclear Receptors; Organ; Pathway interactions; Penetrance; Phagocytes; Phagocytosis; Phenotype; Predisposition; Prevention; Production; Protein Tyrosine Kinase; Proteins; Receptor Activation; Refuse Disposal; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skin; Source; Systemic Lupus Erythematosus; Testing; Therapeutic; Up-Regulation; Work; adiponectin; cooking; cytokine; in vivo; inhibitor/antagonist; macrophage; member; mouse model; novel; receptor; research study; theories

DESCRIPTION (provided by applicant): As many as 1.4 million Americans suffer from chronic autoimmunity and inflammation associated with lupus, where autoantibody generation leads to accumulation of immune complexes that deposit in skin, vasculature, kidneys and other organs causing destructive, debilitating and sometimes life threatening, inflammation. Although lupus is of unknown etiology, it is clearly associated with the inefficient disposal of apoptotic cells, whih are considered the major source of lupus autoantigens. Complement component C1q triggers engulfment of apoptotic cells (efferocytosis), and deficiency in C1q is the strongest known susceptibility factor in lupus. While there has been a lot of attention given to the bridging function of C1q, which is a direct and immediate upregulation of phagocytosis, this is unlikely to explain its role in prevention of autoimmunity because a) it is not specific for apoptotic cell targets; and b) other C1q-related molecules, the collections, also upregulate immediate phagocytosis, but loss of these molecules is not associated with autoimmunity. Our preliminary data suggests an alternative hypothesis: C1q elicits a macrophage phenotype specifically tailored for engulfment of apoptotic cells. The data indicate that this pathway requires C1q- triggered macrophage expression of Mer and its ligand Gas6, an interaction that has been shown to regulate efferocytosis and limit inflammatory gene expression. The purpose of this grant is to define the new mechanism. Specific aim one will investigate the requirement of Mer/Gas6 on C1q-dependent efferocytosis in vivo in mice, and in vitro using primary human phagocytes. Specific aim two will investigate the signal transduction pathway leading to C1q- dependent upregulation of Mer. Adiponectin is a C1q-homologue that regulates efferocytosis and autoimmunity, and preliminary experiments demonstrate a role for adiponectin signaling and nuclear receptor activation in C1q-dependent Mer upregulation. Therefore, components of these signaling pathways will be analyzed using specific inhibitors and mouse models. The consequence of Mer deficiency on C1q/adiponectin-dependent regulation of proinflammatory cytokine production will be investigated in specific aim three using Mer wildtype and knockout mouse cells, as well as primary human phagocytes. The research will describe a novel pathway relevant to autoimmunity which should provide new molecular targets for therapeutics and diagnostics.

描述（由申请人提供）：多达140万美国人患有与狼疮相关的慢性自身免疫性和炎症，自身抗体产生会导致在皮肤，脉管系统，肾脏和其他器官中沉积的免疫复合物的积累，从而导致破坏性，违约，有时甚至威胁生命，炎症，炎症。尽管狼疮是未知的病因，但显然与凋亡细胞的处置效率低下有关，因此被认为是狼疮自身抗原的主要来源。补体成分C1Q触发凋亡细胞的吞噬（肿瘤病），C1q缺乏是狼疮中最强的已知敏感性因子。尽管对C1Q的桥接功能有很大的关注，这是吞噬作用的直接和直接上调，但这不可能解释其在预防自身免疫性中的作用，因为a）它不是针对凋亡细胞靶标的。 b）其他与C1Q相关的分子，集合也会上调立即的吞噬作用，但这些分子的丧失与自身免疫性无关。我们的初步数据提出了另一种假设：C1Q引起了专门针对吞噬凋亡细胞的巨噬细胞表型。数据表明，该途径需要C1Q-触发MER及其配体GAS6的巨噬细胞表达，这种相互作用已显示出来调节胞吞作用并限制炎症基因表达。这笔赠款的目的是定义新机制。特定目标将研究MER/GAS6对小鼠体内C1Q依赖性肿瘤的需求，并使用原代人吞噬细胞在体外进行体外。具体目标两个将研究导致MER的C1Q依赖性上调的信号转导途径。脂联素是一种C1Q-同源物，可调节肾上腺增多症和自身免疫性，初步实验证明了脂联素信号传导和核受体激活在C1Q依赖性MER上调中的作用。因此，将使用特定的抑制剂和小鼠模型分析这些信号通路的组件。 MER缺乏对促炎细胞因子产生的C1Q/脂联素依赖性调节的结果将在特定的目标三中使用MER WildType和敲除小鼠细胞以及原代人吞噬细胞。该研究将描述一种与自身免疫相关的新途径，该途径应为治疗和诊断提供新的分子靶标。