title: The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ.
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.
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Eason
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Kara S
authors.initials: KS
authors.lastname: Bell
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Fraser A
authors.initials: FA
authors.lastname: Marshall
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Rodgers
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pineda
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Christina N
authors.initials: CN
authors.lastname: Steiger
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Lamyaa
authors.initials: L
authors.lastname: Al-Riyami
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: William
authors.initials: W
authors.lastname: Harnett
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Harnett
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D015801:Helminth Proteins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D051745:Protein Kinase C-delta