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A Phosphatidylserine Species Inhibits a Range of TLR- but Not IL-1β-Induced Inflammatory Responses by Disruption of Membrane Microdomains¹

Lisa C. Parker^2,*, Elizabeth C. Prestwich^*, Jon R. Ward, Elizabeth Smythe, Anthony Berry, Martha Triantafilou^¶, Kathy Triantafilou^¶ and Ian Sabroe^*

^* Academic Unit of Respiratory Medicine and Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom; Vaccine Technology Ltd., Horsham, United Kingdom; and ^¶ Infection and Immunity Group, School of Life Sciences, University of Sussex, Sussex, United Kingdom

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded in part by a grant from the Sheffield Hospitals Charitable Trust. I.S. is supported by a MRC Senior Clinical Fellowship (G116/170). K.T. is supported by the Wellcome Trust. J.R.W. is supported by a British Heart Foundation project grant (FS/06/004). This work was also supported by Allergy Therapeutics plc. and Vaccine Technology Ltd. who provided the SAPS (PCT publication no. WO 2008/068621).

² Address correspondence and reprint requests to Dr. Lisa C. Parker, Academic Unit of Respiratory Medicine, L Floor, Royal Hallamshire Hospital, Sheffield S10 2J,F United Kingdom. E-mail address: l.c.parker{at}sheffield.ac.uk

³ Abbreviations used in this paper: PS, phosphatidylserine; CBA, cytometric bead array; FRET, fluorescence resonance energy transfer; LTA, lipoteichoic acid; SAPS, 1-stearoyl-2-arachidonoyl-sn-glycero-3-[phospho-L-serine].