EHD1-mediated Inflammation and Resolution in Atherosclerosis

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.

Grant Number: 7R01HL167107-04
NIH Institute/Center: NIH
Principal Investigator: Bishuang Cai