Human rhinovirus (hRV) is the most common cause of asthma exacerbation characterized by clinical and pathophysiological heterogeneity. Steroid-sensitive, Th2 type-eosinophilic asthma has been somewhat studied, but hRV-induced neutrophilic asthma exacerbation is poorly understood. Here, CCR5 was found to play a role in attenuating neutrophilic airway inflammation in hRV-induced asthma exacerbation using chicken ovalbumin (OVA)-based model. CCR5 deficiency resulted in exacerbated neutrophilic asthmatic responses in airways following hRV infection. CCR5-deficient mice showed enhanced mucus expression and altered expression of tight junction proteins in lung tissues. CCR5-deficient mice were also manifested with influx of CD45+CD11b+Siglec-F+Gr-1+ neutrophils, along with enhanced production of IL-17A, IFN-γ, IL-6, IL-1β cytokines in inflamed tissues. In contrast, CCR5-deficient mice elicited down-regulation of Th2-related cytokine proteins following hRV infection. More interestingly, the lack of CCR5 altered the equilibrium of CD4+FoxP3+ Tregs and IL-17+CD4+ Th17 in inflamed tissues. CCR5-deficient mice showed increased frequency and absolute number of IL-17-producing CD4+ Th17 cells in lung tissues compared to wild-type mice, whereas the reduced infiltration of CD4+FoxP3+ Treg cells was observed. CCR5 deficiency resulted in the skewed production of Th17 and Th1 cytokines in lymph nodes and lungs upon OVA stimulation. Likewise, CCR5-deficient mice showed enhanced expression of Th17-inducing cytokines (IL-1β, IL-6, and TNF-α) in lung tissues. These results imply that CCR5 deficiency facilitates Th17 airway inflammation during hRV-induced asthma exacerbation, along with suppressing Th2 responses. Furthermore, our results suggest that CCR5 attenuates hRV-induced neutrophilic airway inflammation through conserving the equilibrium of CD4+Foxp3+ Treg cells and IL-17+CD4+ Th17 cells in hRV-induced asthma exacerbation.

中文翻译：

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CCR5减轻了因鼻病毒感染而加剧的嗜中性中性气道炎症。

人鼻病毒（hRV）是哮喘加重的最常见原因，其临床和病理生理学异质性为特征。对类固醇敏感的Th2型嗜酸性粒细胞性哮喘已有一定研究，但对hRV诱导的嗜中性哮喘恶化的了解却很少。在这里，使用基于鸡卵清蛋白（OVA）的模型，发现CCR5在hRV诱导的哮喘加重中减轻中性粒细胞气道炎症的作用。CCR5缺乏症导致hRV感染后气道中性粒细胞哮喘反应加剧。CCR5缺陷小鼠在肺组织中显示出增强的黏液表达和紧密连接蛋白表达的改变。CCR5缺陷型小鼠还表现出CD45 + CD11b + Siglec-F + Gr-1 +中性粒细胞大量涌入，以及发炎组织中IL-17A，IFN-γ，IL-6，IL-1β细胞因子的产生增强。相反，在hRV感染后，CCR5缺陷型小鼠引起Th2相关细胞因子蛋白的下调。更有趣的是，CCR5的缺乏改变了发炎组织中CD4 + FoxP3 + Tregs和IL-17 + CD4 + Th17的平衡。与野生型小鼠相比，CCR5缺陷型小鼠肺组织中产生IL-17的CD4 + Th17细胞的频率和绝对数量增加，而CD4 + FoxP3 + Treg细胞的浸润减少。CCR5缺乏症导致OVA刺激后淋巴结和肺中Th17和Th1细胞因子的产生偏斜。同样，CCR5缺陷小鼠在肺组织中显示出Th17诱导细胞因子（IL-1β，IL-6和TNF-α）的增强表达。这些结果表明，在hRV诱发的哮喘加重期间，CCR5缺乏促进Th17气道炎症，以及抑制Th2响应。此外，我们的结果表明，CCR5通过在hRV诱发的哮喘急性发作中保持CD4 + Foxp3 + Treg细胞和IL-17 + CD4 + Th17细胞的平衡来减轻hRV诱导的嗜中性气道炎症。