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Macrophage EHD1 Promotes Inflammation and Stabilizes Sortilin to Accelerate Atherosclerosis
Fanglin Ma1,2,3, Yu Liu1,2,3, Yang Xu4
1Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine (F.M., Y.L., N.G., Y.Z., R.S., B.C.), University of California, Los Angeles (UCLA), Los Angeles, CA.
Circulation Research
|May 21, 2026
Summary
Endocytic regulator EHD1 promotes atherosclerosis by enhancing macrophage inflammation and TNFR2-NF-κB signaling. Deleting EHD1 reduces atherosclerotic lesions and inflammatory responses in macrophages.
Area of Science:
- Cell biology
- Immunology
- Cardiovascular research
Background:
- Macrophages are crucial in atherosclerosis development, regulating immune responses via cell-surface receptors.
- Macrophage receptor regulation by endocytic membrane trafficking is vital but not fully understood.
- The role of endocytic regulator EHD1 in macrophage immune responses and atherosclerosis was investigated.
Purpose of the Study:
- To investigate the role of EHD1 in macrophage immune responses.
- To determine EHD1's contribution to atherosclerosis progression.
- To elucidate the molecular mechanisms by which EHD1 influences macrophage function and atherosclerosis.
Main Methods:
- EHD1 expression analysis in mouse and human atherosclerotic plaques using single-cell RNA sequencing and immunofluorescence.
- Bone marrow transplantation studies in Ldlr-/- mice using Ehd1-/- and wild-type bone marrow cells.
- In vitro studies in bone marrow-derived macrophages, including inflammation signaling and endocytosis assays.
Main Results:
- EHD1 expression increases with atherosclerosis progression in mice and humans.
- EHD1 deletion in macrophages reduces atherosclerotic lesion size and attenuates proinflammatory responses.
- EHD1 accelerates TNFR2 recycling, activates NF-κB signaling, and stabilizes sortilin, a risk factor for atherosclerosis.
Conclusions:
- EHD1 promotes atherosclerosis by enhancing TNFR2-NF-κB signaling and stabilizing sortilin in macrophages.
- EHD1-mediated membrane trafficking plays a significant role in macrophage function during atherosclerosis.
- Targeting EHD1-mediated membrane trafficking offers potential therapeutic strategies for atherosclerosis.
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