Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:136

Article

Gielen, Vera^1,3,4,5  Sykes, Annemarie^1,3,4,5,6  Zhu, Jie^1,3,4,5  Chan, Brian¹  Macintyre, Jonathan^1,3,4,5,6  Regamey, Nicolas⁷  Kieninger, Elisabeth⁷  Gupta, Atul^2,4,5  Shoemark, Amelia^2,4,5  Bossley, Cara^2,4,5  Davies, Jane^2,4,5  Saglani, Sejal^2,4,5  Walker, Patrick⁸  Nicholson, Sandra E.^9,10  Dalpke, Alexander H.⁸  Kon, Onn-Min⁶  Bush, Andrew^2,4,5  Johnston, Sebastian L.^1,3,4,5,6  Edwards, Michael R.^1,3,4,5 

[1] Natl Heart & Lung Inst, Airway Dis Infect Sect, London, England

[2] Natl Heart & Lung Inst, Resp Pediat, London, England

[3] Univ London Imperial Coll Sci Technol & Med, Ctr Resp Infect, London, England

[4] MRC, London, England

[5] Asthma UK Ctr Allerg Mech Asthma, London, England

[6] Imperial Coll Healthcare Natl Hlth Serv Trust, London, England

[7] Univ Bern, Pediat Med, CH-3012 Bern, Switzerland

[8] Heidelberg Univ, Dept Infect Dis Med Microbiol & Hyg, D-69115 Heidelberg, Germany

[9] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia

[10] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

关键词: Rhinovirus;    asthma;    asthma exacerbation;    atopy;    interferon;    innate immunity;    cytokine;    T(H)2 inflammation;    suppressor of cytokine signaling;   

DOI  :  10.1016/j.jaci.2014.11.039

来源: Elsevier

【 摘 要 】

Background: Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-alpha/beta/lambda in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. Objective: We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. Methods: We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. Results: We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. Conclusion: We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.

【 授权许可】

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