Tollip Inhibits ST2 Signaling in Airway Epithelial Cells Exposed to Type 2 Cytokines and Rhinovirus
| Autor: | Max A. Seibold, Azzeddine Dakhama, Julie G. Ledford, Dennis R. Voelker, Reem Al Mubarak, Liwu Li, Hong Wei Chu, Monica Kraft, Nicole Pavelka |
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| Přispěvatelé: | Biological Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Rhinovirus Neutrophils Context (language use) Respiratory Mucosa Biology medicine.disease_cause Airway epithelial cells Neutrophil Activation Proinflammatory cytokine Immunomodulation 03 medical and health sciences 0302 clinical medicine Immune system Th2 Cells medicine Immunology and Allergy Humans Interleukin 8 RNA Small Interfering Receptor Cells Cultured Picornaviridae Infections Type 2 cytokines TOLLIP Interleukin-8 Intracellular Signaling Peptides and Proteins IRAK1 ST2 Interleukin-1 Receptor-Like 1 Protein 030104 developmental biology Interleukin-1 Receptor-Associated Kinases 030228 respiratory system Immunology Tollip Cytokines Research Article Signal Transduction |
| Popis: | The 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. NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1U19AI125357, R01HL122321, R01AI106287, R01HL125128] This 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. |
| Databáze: | OpenAIRE |
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