Oxidized Low-Density Lipoprotein Immune Complexes Stimulate Proinflammatory Changes in Innate and Adaptive Immunity

氧化低密度脂蛋白免疫复合物刺激先天性和适应性免疫的促炎变化

• 批准号: 10338081
• 负责人: Brenna Appleton
• 金额: $ 3.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338081
• 关键词: Adoptive Transfer; Affect; American; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Arteries; Atherosclerosis; Autoimmune Diseases; Binding; Blocking Antibodies; Blood Circulation; Bone Marrow; CD36 gene; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Chronic Disease; Coculture Techniques; Data; Dendritic Cells; Dendritic cell activation; Diabetes Mellitus; Disease; Female; Genetic; ITGAX gene; IgG Receptors; Immune; Immune response; Immunity; In Vitro; Inflammasome; Inflammation; Inflammatory; Injections; Interleukin-1; Knock-out; Lead; Low-Density Lipoproteins; Measures; Mediating; Metabolic; Metabolism; Molecular; Mus; Natural Immunity; Oxides; Pathogenicity; Pathway interactions; Patients; Phenotype; Physiological; Population; Production; Receptor Signaling; Rheumatoid Arthritis; Role; Severity of illness; Signal Transduction; Sterility; Surface Antigens; Systemic Lupus Erythematosus; T cell response; T-Cell Activation; T-Lymphocyte; TLR4 gene; Testing; Work; adaptive immunity; autoinflammatory; conditional knockout; cytokine; experimental study; in vivo; inhibitor/antagonist; knockout gene; macrophage; microbial; oxidized low density lipoprotein; respiratory; response; success; transcriptome sequencing

PROJECT SUMMARY Cardiovascular disease (CVD) affects almost one third of the U.S. population and is responsible for the deaths of approximately 1 million Americans annually. Atherosclerosis, the most common form of CVD, is a disease of sterile inflammation characterized by the accumulation of plaque in the arteries. This is thought to be initiated by the entry and sequestration of low-density lipoprotein (LDL) in the vasculature where it becomes oxidized (oxLDL). Studies show that much of the oxLDL in circulation is bound to specific antibody to form oxLDL immune complexes (oxLDL-ICs) and there is a positive correlation between titers of circulating oxLDL-ICs and atherosclerosis disease severity. Our group has shown that oxLDL-ICs cooperatively signal through Fc gamma receptors (FcRs), Toll-like Receptor 4, and CD36 in murine bone marrow-derived dendritic cells (BMDCs) in vitro to enhance the production of proatherogenic cytokine IL-1. Preliminary data indicate oxLDL-IC pretreated BMDCs enhance Th17 and suppress Th1 responses, relative to oxLDL pretreated BMDCs. However, these differential T cell responses appear to be the result of a separate mechanisms. The role of oxLDL-ICs in vivo is not fully understood, but our lab has shown that elimination of the inhibitory FcR, FcRIIb, on CD11c+ cells is sufficient to increase atherosclerosis in female Ldlr-/- mice. FcRs are expressed on the surface of antigen presenting cells like dendritic cells (DCs) and macrophages, and activating and inhibitory FcRs elicit opposing pro-inflammatory and tolerogenic phenotypes, respectively. As oxLDL-ICs are signaling in part through FcRs, these data provide a mechanism by which oxLDL-IC signaling specifically on DCs could promote atherosclerosis. Furthermore, preliminary data demonstrate oxLDL-IC stimulation induces metabolic changes in BMDCs not seen with free oxLDL. Cells activated by oxLDL-IC are more glycolytic and have an increased spare respiratory capacity. Collectively, these data lead to the hypothesis oxLDL-IC signaling alters DC function resulting in changes in T cell activation and differentiation that are proatherogenic. Aim 1 of this proposal will determine how oxLDL-IC stimulation of DCs alters downstream CD4+ T cell responses by leveraging BMDC/T cell co-cultures with gene knockouts and blocking antibodies, adoptive transfers, and in vivo oxLDL-IC injections. Aim 2 will investigate how oxLDL-IC induced changes in metabolism contribute to DC activation and function using metabolic flux experiments, RNA sequencing, and BMDC/T cell co-cultures with metabolic inhibitors and gene knockouts. Overall, this proposal will define how oxLDL-ICs directly impact DC function and how CD4+ T cells are subsequently influenced. The success of these studies will inform how oxLDL-ICs contribute to sterile inflammation and will broaden our understanding of atherosclerosis and other oxLDL-IC associated autoinflammatory disorders.

项目总结