Defining critical roles for NF-?B p65 and type I interferon in innate immunity to rhinovirus
Defining critical roles for NF-?B p65 and type I interferon in innate immunity to rhinovirus
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DOI：
10.1002/emmm.201201650
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发表时间：
2012-12-01
影响因子：
11.1
通讯作者：
Edwards, Michael R.
中科院分区：
文献类型：
--
作者：
Bartlett, Nathan W.;Slater, Louise;Edwards, Michael R.
NF-的重要性？B活化和缺乏抗病毒干扰素诱导在鼻病毒诱导哮喘加重的发病机制尚不清楚。我们首次在人体和小鼠中提供了鼻病毒感染增强支气管上皮细胞NF-？B p65核表达，NF-？B p65 DNA在肺组织和NF-？b调节的气道炎症。体外抑制NF-？B降低鼻病毒诱导的促炎细胞因子，但不影响I/III型干扰素诱导。鼻病毒感染的p65缺陷小鼠表现出中性粒细胞炎症减轻，但干扰素诱导、抗病毒反应和病毒载量未受影响，这表明NF-？bp65是促炎反应所必需的，但在体内鼻病毒干扰素诱导中是多余的。相反，IFNAR1-/-小鼠表现出增强的中性粒细胞炎症，抗病毒免疫受损，鼻病毒复制增加，表明干扰素信号传导对抗病毒免疫至关重要。因此，我们为鼻病毒感染提供了新的机制见解，并证明了靶向NF-？B p65（抑制炎症但保持抗病毒免疫）和I型IFN信号（增强缺乏的抗病毒免疫）治疗鼻病毒引起的气道疾病加重。参见随附文章http://dx.doi.org/10.1002/emmm.201202032
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