# Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis

> **NIH NIH P01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2020 · $354,006

## Abstract

Project Summary
Hypercholesterolemia and vascular inflammation are among the strongest causative factors in the
development of atherosclerosis and in the progression of early atherosclerotic lesions into advanced
vulnerable plaques. However, it is yet unclear whether vascular cholesterol accumulation directly contributes to
vascular inflammation and, specifically, to polarization of macrophages into inflammatory phenotypes. In this
project, we will investigate two mechanisms, which contribute to cholesterol-mediated inflammatory responses
by macrophages, and will determine their quantitative significance in the development of atherosclerosis in a
mouse model and the translational potential of relevant new biomarkers and therapeutic approaches. In an
atherogenic mechanism, oxidized cholesteryl esters (OxCE) induce dimerization of toll-like receptor-4 (TLR4),
which in turn mediates inflammatory and atherogenic responses in macrophages. In an atheroprotective
mechanism, we have identified the secreted apoA-I binding protein (AIBP) as a factor, which significantly
improves HDL function by accelerating cholesterol efflux, resulting in the disruption of lipid raft-dependent
TLR4 dimerization and reduced inflammatory responses in macrophages. We will test the hypotheses that
OxCE promotes and AIBP inhibits inflammatory macrophage polarization, foam cell formation and
atherosclerosis. We have generated a monoclonal antibody blocking OxCE, as well as systemic and
macrophage-specific Apoa1bp-/- mice to test these hypotheses. In complementary experiments, we will use
infusions of recombinant AIBP and/or an AIBP-expressing adeno-associated virus to achieve increased AIBP
levels in plasma and expect to inhibit atherosclerosis progression. Importantly, synergistic studies with other
PPG Projects will examine the relevance of OxCE and AIBP mechanisms to atherogenic or atheroprotective
functions of different monocyte and T and B cell populations. To translate our findings into clinic, we will use
plasma from Multi-Ethnic Study of Atherosclerosis (MESA) subjects, who have elevated coronary artery
calcium or have experienced major adverse cardiovascular events, to evaluate diagnostic and prognostic value
of new OxCE and AIBP biomarkers. These results will be integrated with other biomarkers identified by the
PPG Investigators. To examine novel therapeutic approaches to restrain cholesterol-induced inflammation, we
will test the hypothesis that raising AIBP in the low-AIBP plasma and blocking OxCE in the high-OxCE plasma
found in MESA populations will reduce plasma's atherogenic effects on human macrophages. The proposed
studies will enhance our mechanistic understanding of cholesterol-mediated inflammation in atherosclerosis
and will advance new biomarker and therapeutic strategies for cardiovascular disease.

## Key facts

- **NIH application ID:** 9940775
- **Project number:** 5P01HL136275-04
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Yury Miller
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,006
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940775

## Citation

> US National Institutes of Health, RePORTER application 9940775, Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis (5P01HL136275-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940775. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*