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

Eason, Russell J. and Bell, Kara S. and Marshall, Fraser A. and Rodgers, David T. and Pineda, Miguel A. and Steiger, Christina N. and Al-Riyami, Lamyaa and Harnett, William and Harnett, Margaret M. (2016) The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ. Scientific Reports, 6. ISSN 2045-2322

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    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, speci cally by suppressing TLR4 signalling to inhibit Th1/Th17-driven in ammation. 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-in ammatory responses, is associated with induction of a low level of autophagic ux, as evidenced by upregulation and tra cking 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 re ect a block in autophagic ux, with these elements predominantly degraded in a proteasomal manner. These data are consistent with autophagic ux acting to homeostatically suppress proin ammatory 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 in ammation, either to promote parasite survival or serendipitously, exhibit therapeutic potential in in ammatory disease.