The response of eosinophils (Eos) to respiratory virus has emerged as an important link between pulmonary infection and allergic asthmatic exacerbations. Eos activate innate immune responses through TLR signaling. In this study, using mouse and human Eos and mice lacking the prolyl isomerase Pin1 selectively in Eos, we show that Pin1 is indispensable for eosinophilopoiesis in the bone marrow (BM) and mature cell function in the presence of TLR7 activation. Unbiased in vivo analysis of mouse models of allergic airway inflammation revealed that TLR7 activation in knockout mice resulted in systemic loss of Eos, reduced IFN production, and an inability to clear respiratory viruses. Consistent with this finding, BM mouse Eos progenitors lacking Pin1 showed markedly reduced cell proliferation and survival after TLR7 activation. Mechanistically, unlike wild-type cells, Pin1 null mouse Eos were defective in the activation of the endoplasmic reticulum stress-induced unfolded protein response. We observed significant reductions in the expression of unfolded protein response components and target genes, aberrant TLR7 cleavage and trafficking, and reduced granule protein production in knockout Eos. Our data strongly suggest that Pin1 is required for BM Eos generation and function during concurrent allergen challenge and viral infection.

译文

嗜酸性粒细胞 (Eos) 对呼吸道病毒的反应已成为肺部感染与过敏性哮喘发作之间的重要联系。Eos通过TLR信号激活先天免疫反应。在这项研究中,使用小鼠和人Eos以及在Eos中选择性地缺乏脯氨酰异构酶Pin1的小鼠,我们表明Pin1对于存在TLR7激活的骨髓 (BM) 中的嗜酸性粒细胞生成和成熟细胞功能是必不可少的。对过敏性气道炎症小鼠模型的无偏体内分析表明,敲除小鼠中的TLR7激活导致Eos的全身性损失,IFN产生减少以及无法清除呼吸道病毒。与这一发现一致,缺乏Pin1的BM小鼠Eos祖细胞在TLR7激活后显示出明显降低的细胞增殖和存活。从机制上讲,与野生型细胞不同,Pin1无效小鼠Eos在内质网应激诱导的未折叠蛋白反应的激活方面存在缺陷。我们观察到基因敲除Eos中未折叠蛋白反应成分和靶基因的表达显着降低,TLR7的异常裂解和运输以及颗粒蛋白的产生减少。我们的数据强烈表明,在同时发生过敏原激发和病毒感染期间,BM Eos的产生和功能需要Pin1。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录