Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Sabelo Hadebe; Frank Kirstein; Kaat Fierens; Kong Chen; Rebecca A. Drummond; Simon Vautier; Sara Sajaniemi; Graeme Murray; David L Williams; Pierre Redelinghuys; Todd A. Reinhart; Beth A.  Fallert Junecko; Jay K. Kolls; Bart N. Lambrecht; Frank Brombacher; Gordon D. Brown

doi:10.1371/journal.pone.0134219

Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Sabelo Hadebe, Frank Kirstein, Kaat Fierens, Kong Chen, Rebecca A. Drummond, Simon Vautier, Sara Sajaniemi, Graeme Murray, David L Williams, Pierre Redelinghuys, Todd A. Reinhart, Beth A. Fallert Junecko, Jay K. Kolls, Bart N. Lambrecht, Frank Brombacher, Gordon D. Brown

Applied Medicine

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Abstract

Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.

Original language	English
Article number	e0134219
Number of pages	17
Journal	PloS ONE
Volume	10
Issue number	8
Early online date	11 Aug 2015
DOIs	https://doi.org/10.1371/journal.pone.0134219
Publication status	Published - 11 Aug 2015

Bibliographical note

Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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10.1371/journal.pone.0134219Licence: CC BY

Microbial Ligand Costimulation Drives Neutrophilic Steroid-Refractory Asthma
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. http://creativecommons.org/licenses/by/4.0/
Final published version, 4.09 MBLicence: CC BY

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Hadebe, S., Kirstein, F., Fierens, K., Chen, K., Drummond, R. A., Vautier, S., Sajaniemi, S., Murray, G., Williams, D. L., Redelinghuys, P., Reinhart, T. A., Fallert Junecko, B. A., Kolls, J. K., Lambrecht, B. N., Brombacher, F., & Brown, G. D. (2015). Microbial ligand costimulation drives neutrophilic steroid-refractory asthma. PloS ONE, 10(8), Article e0134219. https://doi.org/10.1371/journal.pone.0134219

Hadebe, S, Kirstein, F, Fierens, K, Chen, K, Drummond, RA, Vautier, S, Sajaniemi, S, Murray, G, Williams, DL, Redelinghuys, P, Reinhart, TA, Fallert Junecko, BA, Kolls, JK, Lambrecht, BN, Brombacher, F & Brown, GD 2015, 'Microbial ligand costimulation drives neutrophilic steroid-refractory asthma', PloS ONE, vol. 10, no. 8, e0134219. https://doi.org/10.1371/journal.pone.0134219

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title = "Microbial ligand costimulation drives neutrophilic steroid-refractory asthma",

abstract = "Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.",

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AU - Vautier, Simon

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N2 - Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.

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Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Abstract

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