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Pathways of airway oxidant formation by house dust mite allergens and viral RNA converge through myosin motors, pannexons and Toll-like receptor 4.

Zhang, J; Chen, J; Mangat, SC; Perera Baruhupolage, C; Garrod, DR; Robinson, C (2018) Pathways of airway oxidant formation by house dust mite allergens and viral RNA converge through myosin motors, pannexons and Toll-like receptor 4. Immun Inflamm Dis, 6 (2). pp. 276-296. ISSN 2050-4527 https://doi.org/10.1002/iid3.216
SGUL Authors: Robinson, Clive

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Abstract

Introduction Intracellular reactive oxidant species (ROS) are generated in human airway epithelial cells by the prothrombinase action of Group 1 house dust mite (HDM) allergens and by ligation of viral RNA sensor Toll‐like receptors (TLRs). We explored signaling convergence between HDM allergens and TLRs in ROS generation because epithelial cells form the primary barrier against inhaled substances and dictate host responses to allergens and viruses. Methods ROS formation by Calu‐3 human airway cells was studied by measuring dihydrorhodamine 123 oxidation after activation by polyinosinic:polycytidylic acid (to activate TLR3), CL097 (to activate TLR7), a natural mixture of HDM allergens, or BzATP. Results TLR4 activation was identified as an indispensable response element for all stimuli, operating downstream from myosin motor activation, pannexon gating for ATP release and the endogenous activation of prothrombin. Exogenous prothrombin activation by HDM allergens was prevented by SGUL 1733, a novel inhibitor of the proteolytic activity of Group 1 HDM allergens, which thus prevented TLR4 from being activated at source. Conclusions Our data identify for the first time that endogenously‐generated prothrombin and TLR4 form a shared effector mechanism essential to intracellular ROS generation activated by a group 1 HDM allergen (itself a prothrombinase) or by ligation of viral RNA‐sensing TLRs. These stimuli operate a confluent signaling pathway in which myosin motors, gating of pannexons, and ADAM 10 lead to prothrombin‐dependent activation of TLR4 with a recycling activation of pannexons.

Item Type: Article
Additional Information: © 2018 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd. Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Airway epithelium, cysteine protease, house dust mite allergens, pannexons, reactive oxidant species, toll-like receptor 4
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Immun Inflamm Dis
ISSN: 2050-4527
Language: eng
Dates:
DateEvent
11 May 2018Published
15 March 2018Published Online
6 February 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
087650Wellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 29542272
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109617
Publisher's version: https://doi.org/10.1002/iid3.216

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