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.
- asthma mechanisms
- cytokine biology
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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JH and MBS contributed equally.
Contributors Guarantor: MBS. Concept and design: VSRRA, KFC, IM, JH and MBS. Acquisition of data, analysis and interpretation: VSRRA, SPa, GL, NZK, JS, JT, SD, Y-KG, PMH, SPh, EFM, RD, PS, KFC, IM, JH and MBS. Drafting of the manuscript: VSRRA, KFC, IM, EFM, JH and MBS. All authors revised the manuscript critically.
Funding MBS was supported by the University of Technolgy Sydney (UTS) and National Health & Medical Research Council (NHMRC) of Australia Investment Fund. JH and EM were supported in part by a project grant from the NHMRC (1068040), as well as the Lions Rheumatism and Arthritis Medical Research Foundation. JT and SD were supported in part by a project grant from the NHMRC (1142006). PMH is funded by a fellowship and grants from the NHMRC of Australia (1138004, 1179092 and 1175134), Medical Research Future Fund (1201338), Australian Research Council (190100091) and by UTS. U-BIOPRED is supported through an Innovative Medicines Initiative Joint Undertaking (grant agreement number 115010), resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution (www.imi.europa.eu). The funding bodies had no role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.
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.
Provenance and peer review Not commissioned; externally peer reviewed.
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