EHD1-mediated Inflammation and Resolution in Atherosclerosis

EHD1 介导的动脉粥样硬化炎症和消退

• 批准号: 10568133
• 负责人: Bishuang Cai
• 金额: $ 72.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568133
• 关键词: Address; Affect; Anti-Inflammatory Agents; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; C-terminal; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cell surface; Cells; Cholesterol; Chronic; Clinical; Data; Disease; Enzymes; Event; Gene Expression; Goals; Human; Human Genetics; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Interruption; Lesion; Link; Lipids; Lipoproteins; Macrophage; Mediating; Mediator; Membrane; Metalloproteases; Mus; Myelogenous; Necrosis; Pathway interactions; Persons; Phenotype; Play; Population; Positioning Attribute; Process; Protein Family; Protein Tyrosine Kinase; Proteins; Recycling; Research; Research Personnel; Residual state; Resolution; Risk; Role; Testing; Therapeutic; atherosclerotic plaque rupture; cardiovascular risk factor; cell type; cytokine; driving force; human disease; infection risk; inhibition of autophagy; lipid mediator; novel; novel therapeutic intervention; prevent; receptor; retrograde transport; selective expression; single-cell RNA sequencing; sortilin; tissue repair; trafficking; transcriptome sequencing

Project Summary/Abstract Atherosclerotic cardiovascular disease (CVD), a chronic lipoprotein-driven inflammatory disorder, is the leading cause of death worldwide. Conventional lipid-lowering therapies only modestly lower cardiovascular risk in the population due to “residual risk,” thought to be caused by excessive inflammation. Emerging evidence shows that the interruption of inflammation resolution, an active tissue repair process, is a key mechanism that contributes to atherosclerotic plaque progression. Therefore, identifying novel targets that mediate both inflammation and resolution is crucial for developing cardiovascular therapeutic strategies that can both boost resolution and prevent inflammation. As endocytic trafficking is an essential cellular process that regulates macrophage function, we have focused on the role of C-terminal Eps15 homology domain-containing (EHD) family proteins, the key conductors of endocytic trafficking in the immune response of macrophages. The publicly available single-cell RNA sequencing (scRNA-seq) data of macrophage populations in both human and murine atherosclerotic plaques reveal that EHD1 is selectively expressed in inflammatory lesional macrophages compared with other EHD proteins, and our new study shows that EHD1 levels are increased in lesional macrophages from both human and murine plaques as atherosclerosis progresses. These data support an overall proatherogenic role for EHD1 and underscore its relevance to human disease. The overall objective of this proposal is to study the role and the underlying mechanisms of EHD1 in inflammation and resolution in the context of atherosclerosis. Our data suggest that EHD1 impairs inflammation resolution by inducing the ectodomain cleavage of MerTK, an efferocytosis receptor required for timely resolution of inflammation, and aids inflammation by promoting macrophage polarization toward a proinflammatory phenotype. Moreover, we have established a novel link between EHD1 and sortilin, a human genetic risk factor for CVD, by showing that EHD1 silencing decreases sortilin protein levels. The ectodomain of MerTK is cleaved by the metalloproteinase ADAM17, and our preliminary data show that EHD1 enhances ADAM17 on the cell surface, where shedding takes place. Hence, we will test our hypothesis that EHD1 promotes ADAM17 recycling to the cell surface, which leads to MerTK cleavage, defective efferocytosis, impaired inflammation resolution, and plaque necrosis (Aim 1). As autophagy is well known to suppress polarization of proinflammatory macrophages and we found that EHD1 suppresses autophagy, we hypothesize that EHD1 promotes proinflammatory macrophage polarization by suppressing autophagy, leading to inflammatory plaque progression (Aim 2). Finally, we will investigate whether EHD1 stabilizes sortilin and induces inflammatory cytokine secretion by facilitating retrograde transport of sortilin (Aim 3). By exploring the role of EHD1 in atherosclerosis, we hope to bring to the forefront an important new concept regarding EHD1-mediated intracellular trafficking in plaque progression, one that could provide the basis for novel therapeutic strategies to prevent CVD.

项目总结/文摘