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)
|
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 > School of Infection & Immunity |
| 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
Altmetric
Altmetric