Gene knockdown of CCR3 reduces eosinophilic inflammation and the Th2 immune response by inhibiting the PI3K/AKT pathway in allergic rhinitis mice.
Gene knockdown of CCR3 reduces eosinophilic inflammation and the Th2 immune response by inhibiting the PI3K/AKT pathway in allergic rhinitis mice.
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CCR3 基因敲除通过抑制 PI3K/AKT 通路减少过敏性鼻炎小鼠的嗜酸性粒细胞炎症和 Th2 免疫反应
DOI：
10.1038/s41598-022-09467-4
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发表时间：
2022-03-30
影响因子：
4.6
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Yuan J;Liu Y;Yu J;Dai M;Zhu Y;Bao Y;Peng H;Liu K;Zhu X
CCR 3基因在变应性气道炎症如变应性鼻炎（AR）中起关键作用，并且在鼻腔和骨髓中的CCR 3基因之间存在炎症信号联系。然而，骨髓细胞中CCR 3基因对AR的影响尚不清楚。本研究探讨骨髓CCR 3基因在AR小鼠中的作用及其机制。使用Cre-LoxP重组系统产生小鼠骨髓CCR 3基因（CKO）的条件性敲除，并使用聚合酶链反应（PCR）鉴定后代基因型。在CKO和野生型小鼠中建立卵清蛋白诱导的AR模型，以测量嗜酸性粒细胞炎症和Th 2免疫应答。使用特异性PI 3 K/AKT通路抑制剂（Ly 294002）探索以下机制。我们成功地构建和繁殖了纯合子CKO小鼠，并证实了AR小鼠中CCR 3表达和PI 3 K/AKT通路活性的显著增加。骨髓CCR 3基因缺陷导致CCR 3表达和PI 3 K/AKT信号通路活性显著降低，抑制鼻腔组织病理学病变和嗜酸性粒细胞浸润，减少血清中Th 2细胞因子的产生，从而导致AR小鼠过敏症状的缓解。Ly 294002处理也以浓度依赖性方式降低这些炎症指数，并阻断来自CCR 3的炎症信号，但它不影响AR小鼠中CCR 3的高表达。总的来说，我们的研究结果表明，条件性敲除骨髓CCR 3基因可以减少嗜酸性粒细胞炎症和Th 2免疫反应，这可能是由于抑制PI 3 K/AKT通路。
The CCR3 gene plays a critical role in allergic airway inflammation, such as allergic rhinitis (AR), and there is an inflammatory signal link between the nasal cavity and the CCR3 gene in bone marrow. However, the effects of the CCR3 gene in bone marrow cells on AR are not clear. The present study investigated the roles and underlying mechanisms of the bone marrow CCR3 gene in AR mice. Conditional knockout of the bone marrow CCR3 gene (CKO) in mice was generated using the Cre-LoxP recombination system, and offspring genotypes were identified using polymerase chain reaction (PCR). An ovalbumin-induced AR model was established in CKO and wild-type mice to measure eosinophilic inflammation and the Th2 immune response. The following mechanisms were explored using a specific PI3K/AKT pathway inhibitor (Ly294002). We successfully constructed and bred homozygous CKO mice and confirmed a significant increase in CCR3 expression and PI3K/AKT pathway activity in AR mice. Deficiency of the bone marrow CCR3 gene caused a remarkable reduction of CCR3 expression and the PI3K/AKT signaling pathway activity, inhibited histopathological lesions and eosinophil infiltration of the nasal cavity, and reduced the production of Th2 cytokines in serum, which led to the remission of allergic symptoms in AR mice. Ly294002 treatment also decreased these inflammatory indexes in a concentration-dependent manner and blocked inflammatory signals from CCR3, but it did not affect the high expression of CCR3 in AR mice. Collectively, our results suggest that conditional knockout of the bone marrow CCR3 gene can reduce eosinophilic inflammation and the Th2 immune response, which may be due to inhibition of the PI3K/AKT pathway.
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