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A phosphatidylserine species inhibits a range of TLR- but not IL-1β-induced inflammatory responses by disruption of membrane microdomains

Parker, Lisa C., Prestwich, Elizabeth C., Ward, Jon R., Smythe, Elizabeth, Berry, Anthony, Triantafilou, Martha, Triantafilou, Kathy and Sabroe, Ian 2008. A phosphatidylserine species inhibits a range of TLR- but not IL-1β-induced inflammatory responses by disruption of membrane microdomains. The Journal of Immunology 181 (8) , pp. 5606-5617.

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Abstract

TLRs detect conserved molecular patterns that are unique to microbes, enabling tailored responses to invading pathogens and modulating a multitude of immunopathological conditions. We investigated the ability of a naturally occurring stearoyl-arachidonoyl form of phosphatidylserine (SAPS) to inhibit the proinflammatory effects of TLR agonists in models of inflammation investigating the interaction of leukocytes with epithelial and endothelial cells. The responses to LPS of both epithelial and endothelial cells were highly amplified in the presence of PBMCs. Coincubation with SAPS markedly inhibited activation of cocultures by LPS, principally through inhibition of the TLR4 signaling pathway in PBMCs; however, this was not through downmodulation of TLR4 or coreceptor expression, nor was IL-1β-induced cytokine release affected. SAPS also impaired Pam3CSK4 (TLR2/1), Gardiquimod (TLR7/8), and Streptococcus pneumoniae-induced cytokine release, but had only modest effects on poly(I:C) (TLR3)-induced responses. Fluorescence resonance energy transfer analysis of molecular associations revealed that SAPS disrupted the association of both TLR4 and TLR2 with their respective membrane partners that are required for signaling. Thus, our data reinforce the existence and importance of cooperative networks of TLRs, tissue cells, and leukocytes in mediating innate immunity, and identify a novel disrupter of membrane microdomains, revealing the dependence of TLR signaling on localization within these domains.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Publisher: American Association of Immunologists
ISSN: 0022-1767
Last Modified: 04 Jun 2017 03:10
URI: http://orca.cf.ac.uk/id/eprint/17632

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