Tollip Inhibits ST2 Signaling in Airway Epithelial Cells Exposed to Type 2 Cytokines and Rhinovirus

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dc.contributor.authorDakhama, Azzeddineen
dc.contributor.authorAl Mubarak, Reemen
dc.contributor.authorPavelka, Nicoleen
dc.contributor.authorVoelker, Dennisen
dc.contributor.authorSeibold, Maxen
dc.contributor.authorLedford, Julie G.en
dc.contributor.authorKraft, Monicaen
dc.contributor.authorLi, Liwuen
dc.contributor.authorChu, Hong Weien
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2020-06-01T19:38:58Zen
dc.date.available2020-06-01T19:38:58Zen
dc.date.issued2020-01en
dc.description.abstractThe negative immune regulator Tollip inhibits the proinflammatory response to rhinovirus (RV) infection, a contributor to airway neutrophilic inflammation and asthma exacerbations, but the underlying molecular mechanisms are poorly understood. Tollip may inhibit IRAK1, a signaling molecule downstream of ST2, the receptor of IL-33. This study was carried out to determine whether Tollip downregulates ST2 signaling via inhibition of IRAK1, but promotes soluble ST2 (sST2) production, thereby limiting excessive IL-8 production in human airway epithelial cells during RV infection in a type 2 cytokine milieu (e.g., IL-13 and IL-33 stimulation). Tollip- and IRAK1-deficient primary human tracheobronchial epithelial (HTBE) cells and Tollip knockout (KO) HTBE cells were generated using the shRNA knockdown and CRISPR/Cas9 approaches, respectively. Cells were stimulated with IL-13, IL-33, and/or RV16. sST2, activated IRAK1, and IL-8 were measured. A Tollip KO mouse model was utilized to test if Tollip regulates the airway inflammatory response to RV infection in vivo under IL-13 and IL-33 treatment. Following IL-13, IL-33, and RV treatment, Tollip-deficient (vs. -sufficient) HTBE cells produced excessive IL-8, accompanied by decreased sST2 production but increased IRAK1 activation. IL-8 production following IL-13/IL-33/RV exposure was markedly attenuated in IRAK1-deficient HTBE cells, as well as in Tollip KO HTBE cells treated with an IRAK1 inhibitor or a recombinant sST2 protein. Tollip KO (vs. wild-type) mice developed exaggerated airway neutrophilic responses to RV in the context of IL-13 and IL-33 treatment. Collectively, these data demonstrate that Tollip restricts excessive IL-8 production in type 2 cytokine-exposed human airways during RV infection by promoting sST2 production and inhibiting IRAK1 activation. sST2 and IRAK1 may be therapeutic targets for attenuating excessive neutrophilic airway inflammation in asthma, especially during RV infection.en
dc.description.notesThis work was supported by the following NIH grants: 1U19AI125357, R01HL122321, R01AI106287, and R01HL125128. These funding sources were not involved in the preparation of data or the manuscript.en
dc.description.sponsorshipNIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1U19AI125357, R01HL122321, R01AI106287, R01HL125128]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1159/000497072en
dc.identifier.eissn1662-8128en
dc.identifier.issn1662-811Xen
dc.identifier.issue1en
dc.identifier.pmid30928973en
dc.identifier.urihttp://hdl.handle.net/10919/98656en
dc.identifier.volume12en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectTollipen
dc.subjectST2en
dc.subjectAirway epithelial cellsen
dc.subjectRhinovirusen
dc.subjectType 2 cytokinesen
dc.subjectInterleukin-8en
dc.titleTollip Inhibits ST2 Signaling in Airway Epithelial Cells Exposed to Type 2 Cytokines and Rhinovirusen
dc.title.serialJournal of Innate Immunityen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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