Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma.

Allam, VSRR; Pavlidis, S; Liu, G; Kermani, NZ; Simpson, J; To, J; Donnelly, S; Guo, Y-K; Hansbro, PM; Phipps, S; Morand, EF; Djukanovic, R; Sterk, P; Chung, KF; Adcock, I; Harris, J; Sukkar, MB

Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma.

Allam, VSRR Pavlidis, S Liu, G

Kermani, NZ Simpson, J To, J

Donnelly, S

Guo, Y-K Hansbro, PM Phipps, S Morand, EF Djukanovic, R Sterk, P Chung, KF Adcock, I Harris, J Sukkar, MB

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Publisher:: BMJ PUBLISHING GROUP
Publication Type:: Journal Article
Citation:: Thorax, 2023, 78, (7), pp. 661-673
Issue Date:: 2023

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Field	Value	Language
dc.contributor.author	Allam, VSRR
dc.contributor.author	Pavlidis, S
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.contributor.author	Kermani, NZ
dc.contributor.author	Simpson, J
dc.contributor.author	To, J https://orcid.org/0000-0003-3482-4369
dc.contributor.author	Donnelly, S https://orcid.org/0000-0003-2005-3698
dc.contributor.author	Guo, Y-K
dc.contributor.author	Hansbro, PM
dc.contributor.author	Phipps, S
dc.contributor.author	Morand, EF
dc.contributor.author	Djukanovic, R
dc.contributor.author	Sterk, P
dc.contributor.author	Chung, KF
dc.contributor.author	Adcock, I
dc.contributor.author	Harris, J
dc.contributor.author	Sukkar, MB
dc.date.accessioned	2023-08-09T05:00:49Z
dc.date.available	2022-07-15
dc.date.available	2023-08-09T05:00:49Z
dc.date.issued	2023
dc.identifier.citation	Thorax, 2023, 78, (7), pp. 661-673
dc.identifier.issn	0040-6376
dc.identifier.issn	1468-3296
dc.identifier.uri	http://hdl.handle.net/10453/171758
dc.description.abstract	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 asthma.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	BMJ PUBLISHING GROUP
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1138004
dc.relation	http://purl.org/au-research/grants/nhmrc/1142006
dc.relation	http://purl.org/au-research/grants/nhmrc/1179092
dc.relation	http://purl.org/au-research/grants/nhmrc/1175134
dc.relation.ispartof	Thorax
dc.relation.isbasedon	10.1136/thorax-2021-218555
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences
dc.subject.classification	Respiratory System
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3202 Clinical sciences
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Macrophage Migration-Inhibitory Factors
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Asthma
dc.subject.mesh	Inflammation
dc.subject.mesh	Neutrophils
dc.subject.mesh	Annexins
dc.subject.mesh	Neutrophils
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Asthma
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Inflammation
dc.subject.mesh	Annexins
dc.subject.mesh	Macrophage Migration-Inhibitory Factors
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Macrophage Migration-Inhibitory Factors
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Asthma
dc.subject.mesh	Inflammation
dc.subject.mesh	Neutrophils
dc.subject.mesh	Annexins
dc.title	Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma.
dc.type	Journal Article
utslib.citation.volume	78
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - AIMI - Australian Institute for Microbiology & Infection
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2023-08-09T05:00:46Z
pubs.issue	7
pubs.publication-status	Published online
pubs.volume	78
utslib.citation.issue	7

Abstract:

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 asthma.

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http://hdl.handle.net/10453/171758