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The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro

McLaren, James Edward ORCID:, Calder, Claudia Jane, McSharry, Brian P., Sexton, Keith John, Salter, Rebecca Claire, Singh, Nishi N., Wilkinson, Gavin William Grahame ORCID:, Wang, Edward Chung Yern ORCID: and Ramji, Dipak Purshottam ORCID: 2010. The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro. Journal of Immunology 184 (10) , pp. 5827-5834. 10.4049/jimmunol.0903782

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TNF-like protein 1A (TL1A), a TNF superfamily cytokine that binds to death receptor 3 (DR3), is highly expressed in macrophage foam cell-rich regions of atherosclerotic plaques, although its role in foam cell formation has yet to be elucidated. We investigated whether TL1A can directly stimulate macrophage foam cell formation in both THP-1 and primary human monocyte-derived macrophages with the underlying mechanisms involved. We demonstrated that TL1A promotes foam cell formation in human macrophages in vitro by increasing both acetylated and oxidized low-density lipoprotein uptake, by enhancing intracellular total and esterified cholesterol levels and reducing cholesterol efflux. This imbalance in cholesterol homeostasis is orchestrated by TL1A-mediated changes in the mRNA and protein expression of several genes implicated in the uptake and efflux of cholesterol, such as scavenger receptor A and ATP-binding cassette transporter A1. Furthermore, through the use of virally delivered DR3 short-hairpin RNA and bone marrow-derived macrophages from DR3 knockout mice, we demonstrate that DR3 can regulate foam cell formation and contributes significantly to the action of TL1A in this process in vitro. We show, for the first time, a novel proatherogenic role for both TL1A and DR3 that implicates this pathway as a target for the therapeutic intervention of atherosclerosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QP Physiology
R Medicine > RB Pathology
Publisher: American Association of Immunologists
ISSN: 0022-1767
Last Modified: 18 Oct 2022 12:17

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