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.

Fasciola hepatica-Derived Molecules as Regulators of the Host Immune Response

“…Immunomodulatory functions and modes of action have been outlined for ES products from several parasites. The filarial worm Acanthocheilonema viteae releases a glycoprotein called ES-62 that can interfere with DC TLR4 expression by inducing autophagosomal degradation ( 77 ). By inhibiting mast cell responses, ES-62 and its small molecule analogs prevented the excessive inflammatory response in murine models of asthma ( 78 , 79 ).…”

From Christian de Duve to Yoshinori Ohsumi: More to autophagy than just dining at home

“…Consistent with this, autophagy downregulates TCR-coupled NF-κB activation by the highly selective degradation of Bcl10 (but not its binding partner Malt1) [101] , [102] via the TCR-driven K63-polyubiquitination of Bcl10 and its subsequent binding to the autophagy adaptor p62/SQSTM1. Reminiscent of the dual roles of p62 in promoting TLR-stimulated NF-κB and resolving inflammatory cytokine production by autophagy in keratinocytes and DCs [86] , [103] , p62 binding to Bcl-10 was required both for NF-κB activation and its downregulation [101] , [102] : this dual functionality perhaps suggests that the accumulation of autophagosomes following TCR signalling reflects autophagic flux blockade [103] to promote priming of responses, that is alleviated by the fall in mTOR and rise in AMPK activation allowing rapid induction of autophagic flux during the contraction phase of the T cell response.…”

Can Parasitic Worms Cure the Modern World’s Ills?

“…For example, recent studies suggest mTORC2 signalling appears essential and specific to AAM-M2 differentiation and its deficiency in macrophages renders mice incapable of clearing pulmonary infection with N. brasiliensis and prevents their ability to regulate metabolic control of thermogenesis[82]. Moreover, as mTOR and autophagy are counter-regulatory[60], this provides another point of potential intervention by helminths: consistent with its induction of autophagy to limit TLR-mediated inflammation, ES-62 suppresses activation of PI3K/AKT, upstream regulators of mTOR[59,83], whilst Brugia malayi microfilariae inhibit the mTOR pathway and induce autophagy in human DCs[84]. However, the ability of helminths to induce autophagy is not always good news, as the chronic oxidative stress underpinning transformation in hepatocellular carcinoma by the fluke Dicrocoelium dendriticum is associated with induction of autophagic vesicles by its somatic antigens[85].…”

“…Such a key role for MyD88 downregulation in preventing disease is supported by lineage-specific deficiency in the adaptor molecule being sufficient to abrogate lupus-like (B cells)[56, 57] and high fat diet (HFD)-induced cardiovascular (myeloid and endothelial cells)[58] pathologies in inflammatory mouse models. The mechanisms exploited by ES-62 remain to be fully delineated but involve the homeostatic induction of selective autophagy, which normally acts to limit TLR-driven inflammation, to degrade MyD88 and downstream effectors[59,60].…”