Imperial College London
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ProfessorIanAdcock

Faculty of Medicine, National Heart & Lung Institute

Professor of Respiratory Cell & Molecular Biology
 
 
 
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Contact

 

+44 (0)20 7594 7840ian.adcock Website

 
 
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Location

 

304Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Allam:2023:10.1136/thorax-2021-218555,
author = {Allam, VSRR and Pavlidis, S and Liu, G and Kermani, NZ and Simpson, J and To, J and Donnelly, S and Guo, Y-K and Hansbro, PM and Phipps, S and Morand, EF and Djukanovic, R and Sterk, P and Chung, KF and Adcock, I and Harris, J and Sukkar, MB},
doi = {10.1136/thorax-2021-218555},
journal = {Thorax},
pages = {661--673},
title = {Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma},
url = {http://dx.doi.org/10.1136/thorax-2021-218555},
volume = {78},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo.Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity.Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic
AU  - Allam,VSRR
AU  - Pavlidis,S
AU  - Liu,G
AU  - Kermani,NZ
AU  - Simpson,J
AU  - To,J
AU  - Donnelly,S
AU  - Guo,Y-K
AU  - Hansbro,PM
AU  - Phipps,S
AU  - Morand,EF
AU  - Djukanovic,R
AU  - Sterk,P
AU  - Chung,KF
AU  - Adcock,I
AU  - Harris,J
AU  - Sukkar,MB
DO  - 10.1136/thorax-2021-218555
EP  - 673
PY  - 2023///
SN  - 0040-6376
SP  - 661
TI  - Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma
T2  - Thorax
UR  - http://dx.doi.org/10.1136/thorax-2021-218555
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000882445800001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/100886
VL  - 78
ER  -
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