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

Award Number: F31ES030593
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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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 ¿-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$29,265 )
2023	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	001	3	11/23/2022	NON-COMPETING CONTINUATION	-$17,423
2023	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	2	11/23/2022	NON-COMPETING CONTINUATION	-$11,842
														Subtotal = -$29,265

Issue Date FY: 2022 ( Subtotal = -$20,024 )
2022	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	3	7/22/2022	NON-COMPETING CONTINUATION	-$20,024
														Subtotal = -$20,024

Issue Date FY: 2021 ( Subtotal = $37,447 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	3	4/15/2021	NON-COMPETING CONTINUATION	$37,447
														Subtotal = $37,447

Issue Date FY: 2020 ( Subtotal = $36,611 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	2	4/16/2020	NON-COMPETING CONTINUATION	$36,611
														Subtotal = $36,611

Issue Date FY: 2019 ( Subtotal = $35,836 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	1	5/2/2019	NEW	$35,836
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	001	1	5/2/2019	NEW	$0
														Subtotal = $35,836

Grand Total All Awards = $60,605

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

Award Number: F31ES030593

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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