Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes.
Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes.
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DOI：
10.1172/jci.insight.139190
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发表时间：
2021-08-23
期刊：
影响因子：
8
通讯作者：
Kawaguchi A
中科院分区：
文献类型：
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作者：
Lee S;Ishitsuka A;Kuroki T;Lin YH;Shibuya A;Hongu T;Funakoshi Y;Kanaho Y;Nagata K;Kawaguchi A
哮喘是一种与Th 2细胞因子过量产生和肺嗜酸性粒细胞蓄积相关的气道慢性炎症性疾病。尽管类固醇给药阻断了炎性细胞因子的自分泌/旁分泌环，但这种炎症反应仍持续存在，并且哮喘急性发作的详细机制仍不清楚。在这里，我们表明哮喘急性发作是由气道巨噬细胞通过朊病毒样细胞间传递细胞外颗粒（包括ASC蛋白）引发的，ASC蛋白组装炎性小体并介导IL-1β的产生。OVA诱导的过敏性哮喘和相关的IL-1β产生在具有小GT3/Arf 6缺陷的巨噬细胞的小鼠中减轻。细胞外ASC斑点被Arf 6-/-巨噬细胞轻微吞噬，与WT巨噬细胞相比，Arf 6-/-巨噬细胞中IL-1β的产生减少。此外，药理学抑制的Arf 6鸟嘌呤核苷酸交换因子抑制哮喘样过敏性炎症的OVA攻击的WT小鼠。总的来说，细胞外ASC斑点的Arf 6依赖性细胞间传递有助于过敏性炎症的放大和随后的哮喘恶化。
Asthma is a chronic inflammatory disease of the airways associated with excess production of Th2 cytokines and lung eosinophil accumulation. This inflammatory response persists in spite of steroid administration that blocks autocrine/paracrine loops of inflammatory cytokines, and the detailed mechanisms underlying asthma exacerbation remain unclear. Here, we show that asthma exacerbation is triggered by airway macrophages through a prion-like cell-to-cell transmission of extracellular particulates, including ASC protein, that assemble inflammasomes and mediate IL-1β production. OVA-induced allergic asthma and associated IL-1β production were alleviated in mice with small GTPase Arf6-deficient macrophages. The extracellular ASC specks were slightly engulfed by Arf6–/– macrophages, and the IL-1β production was reduced in Arf6–/– macrophages compared with that in WT macrophages. Furthermore, pharmacological inhibition of the Arf6 guanine nucleotide exchange factor suppressed asthma-like allergic inflammation in OVA-challenged WT mice. Collectively, the Arf6-dependent intercellular transmission of extracellular ASC specks contributes to the amplification of allergic inflammation and subsequent asthma exacerbation.
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影响因子：
7
作者：
Place DE;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
30.5
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
82.9
作者：
Sagoo, Pervinder;Garcia, Zacarias;Bousso, Philippe
通讯作者：
Bousso, Philippe
适配器 ASC 具有传播炎症的细胞外活性和“prionoid”活性。
影响因子：
30.5
作者：
通讯作者：
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