Defining critical roles for NF-?B p65 and type I interferon in innate immunity to rhinovirus

被引:67
作者
Bartlett, Nathan W. [1 ,2 ,3 ,4 ]
Slater, Louise [1 ,2 ,3 ,4 ]
Glanville, Nicholas [1 ,2 ,3 ,4 ]
Haas, Jennifer J. [1 ,2 ,3 ,4 ]
Caramori, Gaetano [5 ]
Casolari, Paolo [5 ]
Clarke, Deborah L. [4 ,6 ]
Message, Simon D. [1 ,2 ,3 ,4 ,7 ]
Aniscenko, Julia [1 ,2 ,3 ,4 ]
Kebadze, Tatiana [1 ,2 ,3 ,4 ]
Zhu, Jie [1 ,2 ,3 ,4 ]
Mallia, Patrick [1 ,2 ,3 ,4 ,7 ]
Mizgerd, Joseph P. [8 ]
Belvisi, Maria [4 ,6 ]
Papi, Alberto [5 ]
Kotenko, Sergei V. [9 ]
Johnston, Sebastian L. [1 ,2 ,3 ,4 ,7 ]
Edwards, Michael R. [1 ,2 ,3 ,4 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Natl Heart Lung Inst, Dept Resp Med, London, England
[2] MRC, London, England
[3] Asthma UK Ctr Allerg Mech Asthma, London, England
[4] Univ London Imperial Coll Sci Technol & Med, Ctr Resp Infect, London, England
[5] Univ Ferrara, Sez Malattie Apparato Resp, Ctr Studio Malattie Infiammatorie Cron Vie Aeree, I-44100 Ferrara, Italy
[6] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England
[7] Imperial Coll Healthcare Natl Hlth Serv Trust, London, England
[8] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA
[9] UMDNJ New Jersey Med Sch, Univ Hosp Canc Ctr, Dept Biochem & Mol Biol, Newark, NJ USA
基金
英国惠康基金;
关键词
asthma; inflammation; interferon; NF-kappaB; rhinovirus; BRONCHIAL EPITHELIAL-CELLS; DOUBLE-STRANDED-RNA; FACTOR-KAPPA-B; THYMIC STROMAL LYMPHOPOIETIN; ALLERGIC AIRWAY INFLAMMATION; TRANSCRIPTION FACTOR; GENE-EXPRESSION; ASTHMA EXACERBATIONS; VIRAL-INFECTIONS; VIRUS INDUCTION;
D O I
10.1002/emmm.201201650
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The importance of NF-?B activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-?B p65 nuclear expression, NF-?B p65 DNA binding in lung tissue and NF-?B-regulated airway inflammation. In vitro inhibition of NF-?B reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-?B p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1-/- mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-?B p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases. See accompanying article http://dx.doi.org/10.1002/emmm.201202032
引用
收藏
页码:1244 / 1260
页数:17
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