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

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2020 · $30,260

## Abstract

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.

## Key facts

- **NIH application ID:** 10066029
- **Project number:** 1F31HL154569-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Brenna Appleton
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,260
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066029

## Citation

> US National Institutes of Health, RePORTER application 10066029, Oxidized Low-Density Lipoprotein Immune Complexes Stimulate Proinflammatory Changes in Innate and Adaptive Immunity (1F31HL154569-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10066029. Licensed CC0.

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