# Fc Receptors in Atherosclerosis: Linking Innate and Adaptive Immunity.

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Cardiovascular disease (CVD) accounts for the deaths of approximately 1 million Americans annually. Studies
show that Veterans over the age of 50 are at increased risk for CVD. Atherosclerosis, the most common form
of CVD, is a disease of sterile inflammation characterized by accumulation of plaque in the arteries. Initially,
low density lipoproteins (LDL) accumulates in the vasculature where they subsequently become oxidized
(oxLDL) and cause damage to local tissue. This results in activation of innate and adaptive immunity and
production of oxLDL-specific IgG. Titers of oxLDL-specific antibodies and the resulting immune complexes
(oxLDL-ICs) are known to correlate with disease severity, it is unknown if oxLDL-ICs play a role in disease
pathogenesis. ICs can regulate inflammation in atherosclerosis by interacting with Fc gamma receptors
(FcgRs) expressed on the surface of DCs. Activating (FcgRI/III) and inhibitory (FcgRIIb) FcgRs mediate
opposing functions in DCs, shifting the balance between pro-inflammatory DC activation and tolerogenic
responses. Our published studies demonstrate that oxLDL-ICs prime the inflammasome more robustly than
free oxLDL. This was primarily through induction of FcgR and TLR cross talk activating the Card9, Malt1,
BCL10 complex to amplify NF-B nuclear translocation. In addition, absence of the inhibitory FcgRIIb on
CD11c+ cells increased atherosclerosis in female but not male Ldlr-/- mice and injection of Ldlr-/- mice with
oxLDL-ICs increases plaque size. Preliminary data suggest that oxLDL-ICs may license DCs to promote TH17
responses and inhibit IFN-g production by TH1 cells. The increase in IL-17 producing T cells is dependent on
IL-1b while decreased IFN-g is likely due to increased IL-23 in response to oxLDL-ICs. These data suggest
that oxLDL-ICs can act as endogenous danger signals, or DAMPs, and have the ability to shape the
inflammatory response in atherosclerosis. Using both in vitro and in vivo models, the long term goal of this
study is to determine the mechanisms by which oxLDL-ICs signaling through FcgRs modulate immunity in
atherosclerosis. We hypothesize that 1) oxLDL-ICs licence DCs to enhance pro-inflammatory CD4+ T cell
responses through mechanisms involving epigenetics and metabolism; 2) oxLDL-ICs potentiate inflammation
in atherosclerosis via trained immunity in DCs, and 3) many of these responses are dependent on sex-
hormones. Being afforded the opportunity to test this hypothesis will allow us to continue to make “big picture”
conclusions regarding the role of oxLDL-ICs in CVD. In addition to hypothesis-driven studies, we will conduct
metabolomic and epigenetic studies that will allow us to make novel and innovative hypotheses. Understanding
the pathological relevance of molecules known to accumulate and positively correlate with CVD severity is
vital, and this avenue of research has important therapeutic potential for Veterans. Approximately 25% of the
more than 8 million current Veterans Affa...

## Key facts

- **NIH application ID:** 10450688
- **Project number:** 5I01BX005333-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** AMY S MAJOR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450688

## Citation

> US National Institutes of Health, RePORTER application 10450688, Fc Receptors in Atherosclerosis: Linking Innate and Adaptive Immunity. (5I01BX005333-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450688. Licensed CC0.

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