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

Venkata Sita Rama Raju Allam^{1

2}, Stelios Pavlidis^{3

4}, Gang Liu⁵, Nazanin Zounemat Kermani³, Jennifer Simpson⁶, Joyce To⁷, Sheila Donnelly⁷, Yi-Ke Guo³, Philip M Hansbro⁵, Simon Phipps⁶, Eric F Morand⁸, Ratko Djukanovic⁹, Peter Sterk¹⁰, Kian Fan Chung^{11

12}, Ian Adcock^{11

12}, James Harris^#⁸, Maria B Sukkar^#¹³

Affiliations

¹ Graduate School of Health, Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia.
² Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
³ Data Science Institute, Imperial College London, London, UK.
⁴ Computational Sciences, Janssen Research and Development, High Wycombe, UK.
⁵ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia.
⁶ Respiratory Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁷ School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.
⁸ Centre for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia.
⁹ NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
¹⁰ Department of Respiratory Medicine, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.
¹¹ Airways Disease, National Heart & Lung Institute, Imperial College London, London, UK.
¹² Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, UK.
¹³ Graduate School of Health, Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia maria.sukkar@outlook.com.

^# Contributed equally.

PMID: 36344253
DOI: 10.1136/thorax-2021-218555

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

Venkata Sita Rama Raju Allam et al. Thorax. 2023 Jul.

. 2023 Jul;78(7):661-673.

doi: 10.1136/thorax-2021-218555. Epub 2022 Nov 7.

Authors

Affiliations

¹ Graduate School of Health, Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia.
² Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
³ Data Science Institute, Imperial College London, London, UK.
⁴ Computational Sciences, Janssen Research and Development, High Wycombe, UK.
⁵ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia.
⁶ Respiratory Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁷ School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.
⁸ Centre for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia.
⁹ NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
¹⁰ Department of Respiratory Medicine, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.
¹¹ Airways Disease, National Heart & Lung Institute, Imperial College London, London, UK.
¹² Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, UK.
¹³ Graduate School of Health, Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia maria.sukkar@outlook.com.

^# Contributed equally.

PMID: 36344253
DOI: 10.1136/thorax-2021-218555

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.

Keywords: asthma; asthma mechanisms; cytokine biology.

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Conflict of interest statement

Competing interests: VSRRA, SPa, GL, NZK, JS, JT, SD, Y-KG, PMH, SPh, JH and MBS have nothing to disclose. EFM reports grants from Janssen, Bristol Myers Squibb, UCB, Merck Serono and Eli Lilly outside the submitted work. In addition, EFM has patents 7,709,514 and 7,863,313 issued. KFC has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim and TEVA regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. IA and PS report grants from the public private European Union Innovative Medicines Initiative during the conduct of the study. RD reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA; consultation for TEVA and Novartis as member of advisory boards; and participation in a scientific discussion about asthma organised by GlaxoSmithKline. RD is a cofounder and current consultant and has shares in Synairgen, a University of Southampton spin-out company.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous