IL-33/ST2 signalling and crosstalk with FcεRI and TLR4 is targeted by the parasitic worm product, ES-62

Ball, D., Al-Riyami, L., Harnett, W. and Harnett, M. (2018) IL-33/ST2 signalling and crosstalk with FcεRI and TLR4 is targeted by the parasitic worm product, ES-62. Scientific Reports, 8, 4497. (doi: 10.1038/s41598-018-22716-9) (PMID:29540770) (PMCID:PMC5852134)

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ES-62 is a secreted parasitic worm-derived immunomodulator that exhibits therapeutic potential in allergy by downregulating aberrant MyD88 signalling to normalise the inflammatory phenotype and mast cell responses. IL-33 plays an important role in driving mast cell responses and promoting type-2 allergic inflammation, particularly with respect to asthma, via MyD88-integrated crosstalk amongst the IL-33 receptor (ST2), TLR4 and FcεRI. We have now investigated whether ES-62 targets this pathogenic network by subverting ST2-signalling, specifically by characterising how the functional outcomes of crosstalk amongst ST2, TLR4 and FcεRI are modulated by the worm product in wild type and ST2-deficient mast cells. This analysis showed that whilst ES-62 inhibits IL-33/ST2 signalling, the precise functional modulation observed varies with receptor usage and/or mast cell phenotype. Thus, whilst ES-62’s harnessing of the capacity of ST2 to sequester MyD88 appears sufficient to mediate its inhibitory effects in peritoneal-derived serosal mast cells, downregulation of MyD88 expression appears to be required to dampen the higher levels of cytokine production typically released by bone marrow-derived mucosal mast cells.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Harnett, Professor William
Authors: Ball, D., Al-Riyami, L., Harnett, W., and Harnett, 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 (Online):2045-2322
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Scientific Reports 7:4497
Publisher Policy:Reproduced under a Creative Commons License

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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 (WELLCOTR)086852/Z/08/ZIII -IMMUNOLOGY