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Macrophage migratio...
Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma
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- Allam, Venkata (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Univ Technol Sydney, Fac Hlth, Grad Sch Hlth, Sydney, NSW, Australia.
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- Pavlidis, Stelios (author)
- Imperial Coll London, Data Sci Inst, London, England.;Janssen Res & Dev, Computat Sci, High Wycombe, England.
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- Liu, Gang (author)
- Centenary Inst, Ctr Inflammat, Sydney, NSW, Australia.;Univ Technol Sydney, Sydney, NSW, Australia.
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- Kermani, Nazanin Zounemat (author)
- Imperial Coll London, Data Sci Inst, London, England.
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- Simpson, Jennifer (author)
- QIMR Berghofer Med Res Inst, Resp Immunol, Brisbane, Qld, Australia.
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- To, Joyce (author)
- Univ Technol Sydney, Fac Sci, Sch Life Sci, Sydney, NSW, Australia.
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- Donnelly, Sheila (author)
- Univ Technol Sydney, Fac Sci, Sch Life Sci, Sydney, NSW, Australia.
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- Guo, Yi-Ke (author)
- Imperial Coll London, Data Sci Inst, London, England.
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- Hansbro, Philip M. (author)
- Centenary Inst, Ctr Inflammat, Sydney, NSW, Australia.;Univ Technol Sydney, Sydney, NSW, Australia.
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- Phipps, Simon (author)
- QIMR Berghofer Med Res Inst, Resp Immunol, Brisbane, Qld, Australia.
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- Morand, Eric F. (author)
- Monash Univ, Ctr Inflammatory Dis, Melbourne, Vic, Australia.
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- Djukanovic, Ratko (author)
- Univ Southampton, Fac Med, NIHR Southampton Biomed Res Ctr, Clin & Expt Sci, Southampton, England.
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- Sterk, Peter (author)
- Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Resp Med, Amsterdam, Netherlands.
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- Chung, Kian Fan (author)
- Imperial Coll London, Natl Heart & Lung Inst, Airways Dis, London, England.
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- Adcock, Ian (author)
- Imperial Coll London, Natl Heart & Lung Inst, Airways Dis, London, England.
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- Harris, James (author)
- Monash Univ, Ctr Inflammatory Dis, Melbourne, Vic, Australia.
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- Sukkar, Maria B. (author)
- Univ Technol Sydney, Fac Hlth, Grad Sch Hlth, Sydney, NSW, Australia.
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(creator_code:org_t)
- 2022-11-07
- 2023
- English.
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In: Thorax. - : BMJ Publishing Group Ltd. - 0040-6376 .- 1468-3296. ; 78:7, s. 661-673
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)
Keyword
- asthma
- asthma mechanisms
- cytokine biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Allam, Venkata
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Pavlidis, Stelio ...
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Liu, Gang
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Kermani, Nazanin ...
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Simpson, Jennife ...
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To, Joyce
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show more...
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Donnelly, Sheila
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Guo, Yi-Ke
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Hansbro, Philip ...
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Phipps, Simon
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Morand, Eric F.
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Djukanovic, Ratk ...
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Sterk, Peter
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Chung, Kian Fan
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Adcock, Ian
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Harris, James
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Sukkar, Maria B.
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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MEDICAL AND HEAL ...
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Thorax
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Uppsala University