Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells

内皮细胞和炎症细胞的局部补体合成和信号传导

• 批准号: 8373385
• 负责人: MELVIN EDWARD MEDOF
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373385
• 关键词: Anaphylatoxins; Antiatherogenic; Atherosclerosis; Attenuated; Biological; Blood Coagulation Factor; Blood Vessels; Bone Marrow Transplantation; C5a anaphylatoxin receptor; CD55 Antigens; Cell Proliferation; Cell Survival; Cell physiology; Cell surface; Cells; Coagulants; Collaborations; Complement; Complement 3 Convertase; Complement 3a; Complement 3b; Complement 5a; Complement Membrane Attack Complex; Coronary Arteriosclerosis; Coronary artery; Data; Dendritic Cells; Deposition; Development; Disease; Down-Regulation; Employee Strikes; Endothelial Cells; Event; Fibroblast Growth Factor; G Protein-Coupled Receptor Signaling; GKLF protein; Generations; Genes; Glean; Growth; Growth Factor; Hematopoietic; Homologous Gene; Human; Hypoxia; Immune; Immune Cell Activation; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Injury; Knowledge; Laboratories; Lead; Leukocytes; Link; Liver; Mediating; Molecular; Mus; Myeloid Cells; Myocardial Infarction; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Platelet-Derived Growth Factor; Play; Prevention; Process; Production; Regulation; Role; Serum; Signal Transduction; Smooth Muscle Myocytes; Staging; Stroke; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Thrombosis; Up-Regulation; Vascular Endothelial Cell; Work; acute coronary syndrome; atherogenesis; atherothrombosis; autocrine; base; cell injury; cell type; cytokine; improved; in vivo; inhibitor/antagonist; insight; macrophage; migration; monocyte; neutrophil; novel; prevent; research study; response; response to injury; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): Inflammatory cell influx and vascular cell proliferation underlie atherosclerotic progression and set the stage for thrombosis, which culminates in myocardial infarction and stroke. While many cell surface molecules and inflammatory mediators have been implicated in this self-perpetuating process, the mechanisms that drive inflammation and proliferation remain incompletely characterized. In recent work, we have found that vascular endothelial cells (ECs) and smooth muscle cells (SMCs) as well as monocytes/macrophages (m¿s) locally produce C3a and C5a activation fragments and that these anaphylatoxins interact with upregulated C3a and C5a receptors (C3aR and C5aR) on ECs/SMCs/m¿s. Our studies show that amplification of this signal transduction is what drives SMC/m¿ proliferation and evokes m¿ inflammatory cytokine production. This insight derived from our studies of immune cell activation which uncovered the previously unrecognized fact that local complement synthesis by interacting dendritic cells (DCs) and T cells is an early event in T cell activation and that the resulting C3a/C5a-C3aR/C5aR interactions play a requisite role in T cell proliferation and effector cytokine production. These studies in immune cells further showed that C3aR/C5aR signaling operates tonically to maintain T cell viability and suppress innate cytokine production. Importantly, our studies in ECs/SMCs/m¿s show that C3aR/C5aR signal transduction operates tonically as in immune cells. Our work has shown that the generation of C3a/C5a from locally synthesized complement by ECs/SMCs/m¿s, like that from immune cells, is regulated by the cell surface C3/C5 convertase inhibitor DAF, and our studies show that DAF expression is controlled transcriptionally by Kruppel-like factor 4 (KLF4). In work with the Simon group, we have found that C3aR/C5aR signaling is what drives the neointimal response to EC injury. Our preliminary studies show that the mechanism underlying this effect is that amplified C3aR/C5aR signal transduction is essential for growth induction by PDGF and VEGF, factors important in both the EC response to injury and atherogenesis. Importantly, our recent work now implicates C3aR/C5aR signaling contributing to the anti- coagulant state of the vasculature. The central hypothesis of this project is that local complement synthesis and autocrine C3aR/C5aR signaling regulates vascular cell responses to injury, which in turn contributes the development of atherosclerosis and thrombosis. In this proposal, we will: 1) Characterize the role of C3aR/C5aR signaling in vascular inflammation, proliferation, and neointimal formation; 2) Establish the importance of autocrine C3aR/C5aR signal transduction in atherothrombosis; and 3) Define the link between suppressed C3aR/C5aR signaling by DAF and the anti-atherogenic/anti-thrombotic effects of KLF4. We believe the studies will provide a new window into processes involved in atherothrombosis and that the insights derived from them will identify important therapeutic targets. PUBLIC HEALTH RELEVANCE: Much is known about the processes that cause atherosclerosis and its occlusive complications that lead to heart attack and stroke. Knowledge of how these processes are controlled, however, is lacking. Our laboratory has uncovered the fact that one of these missing links is a novel cellular pathway that we recently showed is critically involved in regulating immune responses. Its further characterization in vasculature should lead to more effective prevention as well as improved treatment of atherosclerosis, heart attack, and stroke.

描述（由申请人提供）：炎症细胞内流和血管细胞增殖是动脉粥样硬化进展的基础，并为血栓形成奠定了基础，最终导致心肌梗死和中风。虽然许多细胞表面分子和炎症介质都参与了这种自我延续的过程，但驱动炎症和增殖的机制仍然不完全明确。在最近的研究中，我们发现血管内皮细胞（ECs）和平滑肌细胞（SMCs）以及单核/巨噬细胞（m¿s）局部产生C3a和C5a激活片段，这些过敏毒素与ECs/SMCs/m¿s上上调的C3a和C5a受体（C3aR和C5aR）相互作用。我们的研究表明，这种信号转导的放大是驱动SMC/m细胞增殖和引起炎性细胞因子产生的原因。这一见解来源于我们对免疫细胞激活的研究，该研究揭示了以前未被认识到的事实，即通过树突状细胞（dc）和T细胞相互作用的局部补体合成是T细胞激活的早期事件，并且由此产生的C3a/C5a-C3aR/C5aR相互作用在T细胞增殖和效应细胞因子的产生中起着必要的作用。这些免疫细胞的研究进一步表明，C3aR/C5aR信号通路在维持T细胞活力和抑制先天细胞因子产生方面发挥着积极作用。重要的是，我们在ECs/SMCs/m¿s中的研究表明，C3aR/C5aR信号转导与免疫细胞一样具有强直性。我们的研究表明，ECs/SMCs/m¿s局部合成补体产生C3a/C5a，与免疫细胞一样，受细胞表面C3/C5转化酶抑制剂DAF的调节，我们的研究表明DAF的表达受kkrupel样因子4 （KLF4）的转录控制。在与Simon小组的合作中，我们发现C3aR/C5aR信号是驱动EC损伤的新内膜反应的原因。我们的初步研究表明，这种效应的机制是C3aR/C5aR信号转导的扩增对于PDGF和VEGF的生长诱导至关重要，而PDGF和VEGF在EC对损伤和动脉粥样硬化的反应中都很重要。重要的是，我们最近的工作现在暗示C3aR/C5aR信号有助于血管系统的抗凝状态。该项目的中心假设是局部补体合成和自分泌C3aR/C5aR信号调节血管细胞对损伤的反应，进而促进动脉粥样硬化和血栓形成。在本文中，我们将：1)表征C3aR/C5aR信号在血管炎症、增殖和新生内膜形成中的作用；2)确立自分泌C3aR/C5aR信号转导在动脉粥样硬化血栓形成中的重要性；3)明确DAF抑制C3aR/C5aR信号传导与KLF4抗动脉粥样硬化/抗血栓作用之间的联系。我们相信这些研究将为动脉粥样硬化形成过程提供一个新的窗口，并且从中获得的见解将确定重要的治疗靶点。