# Omega-3 Fatty Acid Suppression of Silica-induced Inflammasome Activation in a Novel Alveolar Macrophage Model

> **NIH NIH F31** · MICHIGAN STATE UNIVERSITY · 2020 · $36,611

## Abstract

ABSTRACT
The exposome plays a critical role in the development of autoimmune and inflammatory diseases. In this pro-
posal, I will address the role of the dietary ω-3 fatty acid docosahexaenoic acid (DHA) in protecting against
inflammation induced by the respirable toxicant crystalline silica (cSiO2). Previously, our laboratory found that
supplementation with DHA dose-dependently decreased levels of several features of cSiO2-triggered autoim-
munity in a lupus-prone mouse model. A key event in the development of systemic inflammation in this model is
cSiO2-induced toxicity of the alveolar macrophage (AMph), which involves activation of the NLRP3 inflam-
masome and release of potent IL-1 cytokines. The current literature and my preliminary experiments suggest
that DHA and its metabolites, known as specialized proresolving mediators (SPMs), may attenuate this re-
sponse. Activation of the NLRP3 inflammasome, which is implicated in many inflammatory and autoimmune
conditions, requires an initial priming step, during which NF-kB family transcription factors upregulate inflam-
masome components and pro-IL-1 cytokines. Anti-inflammatory G-protein coupled receptors (GPCRs) have
been identified that bind DHA or SPMs and inhibit NF-kB activation. However, in vitro elucidation of the molecular
events of DHA protection in AMph is limited by the low number of cells attainable from a single mouse (~105).
To address this, I used Max Planck Institute (MPI) cells. MPI cells are a self-renewing macrophage cell line
derived by culturing fetal mouse livers in GM-CSF-supplemented medium and are phenotypically similar to
AMph. My preliminary data show that IL-1 cytokine release in response to LPS-priming and cSiO2 treatment is
attenuated by DHA supplementation. I propose that DHA supplementation increases DHA in the cell membrane
of MPI cells, which can be released and metabolized to SPMs. Free DHA and its SPMs can activate anti-inflam-
matory GPCRs in an autocrine or paracrine manner to attenuate NF-kB signaling, which I hypothesize is a pri-
mary mechanism by which they protect against cSiO2-induced inflammation. In Aim 1, the phospholipid incorpo-
ration of DHA will be measured, and then effects of DHA on IL-1 cytokine release and NF-kB activation will be
assessed. I will also treat cells with chemical agonists, antagonists, and siRNA for specific GPCRs to verify their
role in DHA signaling. In Aim 2, the lipid metabolite profile of cells supplemented with DHA will be measured. I
will then determine the extent to which SPMs suppress NF-kB activation and IL-1 cytokine release. Lastly, chem-
ical antagonists and siRNA will be used to investigate the involvement of proposed SPM receptors. These ex-
periments will be performed in a supportive environment with the necessary resources to accomplish these ob-
jectives. My comprehensive training plan provides personal and professional development, which will assist me
in becoming a successful independent researcher.

## Key facts

- **NIH application ID:** 9926082
- **Project number:** 5F31ES030593-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Kathryn Alexandria Wierenga
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,611
- **Award type:** 5
- **Project period:** 2019-05-16 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926082

## Citation

> US National Institutes of Health, RePORTER application 9926082, Omega-3 Fatty Acid Suppression of Silica-induced Inflammasome Activation in a Novel Alveolar Macrophage Model (5F31ES030593-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9926082. Licensed CC0.

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