The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosmal degradation of TLR-transducers, as exemplified by PKCδ

Eason, R. J., Bell, K. S., Marshall, F. A., Rodgers, D. T., Pineda, M., Steiger, C. N., Al-Riyami, L., Harnett, W. and Harnett, M. M. (2016) The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosmal degradation of TLR-transducers, as exemplified by PKCδ. Scientific Reports, 6, 37276. (doi:10.1038/srep37276) (PMID:27869138) (PMCID:PMC5116678)

[img]
Preview
Text
130671.pdf - Published Version
Available under License Creative Commons Attribution.

2MB

Abstract

We have previously shown that ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae targets dendritic cell (DC) responses, specifically by suppressing TLR4 signalling to inhibit Th1/Th17-driven inflammation. We have now investigated the molecular mechanisms underpinning such immunomodulation and show here that ES-62-mediated downregulation of protein kinase C-δ (PKC-δ), a TLR4-associated signalling mediator required for full activation of LPS-driven pro-inflammatory responses, is associated with induction of a low level of autophagic flux, as evidenced by upregulation and trafficking of p62 and LC3 and their consequent autophagolysosomal degradation. By contrast, the classical TLR4 ligand LPS, strongly upregulates p62 and LC3 expression but under such canonical TLR4 signalling this upregulation appears to reflect a block in autophagic flux, with these elements predominantly degraded in a proteasomal manner. These data are consistent with autophagic flux acting to homeostatically suppress proinflammatory DC responses and indeed, blocking of PKC-δ degradation by the autophagolysosomal inhibitors, E64d plus pepstatin A, results in abrogation of the ES-62-mediated suppression of LPS-driven release of IL-6, IL-12p70 and TNF-α by DCs. Thus, by harnessing this homeostatic regulatory mechanism, ES-62 can protect against aberrant inflammation, either to promote parasite survival or serendipitously, exhibit therapeutic potential in inflammatory disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Harnett, Professor William and Pineda, Dr Miguel
Authors: Eason, R. J., Bell, K. S., Marshall, F. A., Rodgers, D. T., Pineda, M., Steiger, C. N., Al-Riyami, L., Harnett, W., and Harnett, M. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Published Online:21 November 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Scientific Reports 6:37276
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOME)086852/Z/08/ZIII -IMMUNOLOGY