The second-generation tyrosine kinase inhibitor afatinib inhibits IL-1β secretion via blocking assembly of NLRP3 inflammasome independent of epidermal growth factor receptor signaling in macrophage.
The second-generation tyrosine kinase inhibitor afatinib inhibits IL-1β secretion via blocking assembly of NLRP3 inflammasome independent of epidermal growth factor receptor signaling in macrophage.
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DOI：
10.1016/j.molimm.2022.11.009
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发表时间：
2022-12
影响因子：
3.6
通讯作者：
Shujun Xie;Jiafeng Liang;Yanyan Zhao;Jingjing Zhang;X. Chen;Hong Jiang;Zhen Zhang;Shenglin Ma;Shirong Zhang
中科院分区：
文献类型：
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作者：
Shujun Xie;Jiafeng Liang;Yanyan Zhao;Jingjing Zhang;X. Chen;Hong Jiang;Zhen Zhang;Shenglin Ma;Shirong Zhang
慢性炎症可导致多种恶性肿瘤的发生，而炎症消退不充分在肿瘤的侵袭、进展和转移中起着至关重要的作用。阿法替尼是第二代酪氨酸激酶抑制剂，靶向非小细胞肺癌中的表皮生长因子受体。很少有研究显示阿法替尼与先天免疫系统（尤其是巨噬细胞）相关。我们的研究表明，阿法替尼可以剂量依赖性方式阻断巨噬细胞中NLRP 3炎性体的活化，并且阿法替尼可以阻止NLRP 3炎性体的组装。此外，阿法替尼可抑制NLRP 3炎性小体激活，而不依赖于EGFR信号传导。此外，阿法替尼能够减轻体内LPS诱导的脓毒症。这些研究为阿法替尼作为非小细胞肺癌或其他肿瘤及NLRP 3相关疾病的治疗药物提供了重要的实验证据，并探索了阿法替尼在巨噬细胞中的新靶点。
Chronic inflammation might lead to many malignancies, and inadequate resolution could play a crucial role in tumor invasion, progression and metastases. Afatinib is a second-generation tyrosine kinase inhibitor targeting epidermal growth factor receptor in non-small cell lung cancer. Few studies showed the correlation of afatinib and the innate immune system especially macrophage. Our study showed that afatinib could block the activation of NLRP3 inflammasome in a dose-dependent manner in macrophage, and that afatinib could prevent the assembly of NLRP3 inflammasome. Besides, afatinib could inhibit NLRP3 inflammasome activation independent of EGFR signaling. Moreover, afatinib was able to alleviate the LPS-induced sepsisin vivo. These investigations provide significant experimental evidence in afatinib as therapeutic drug for non-small cell lung cancer or other tumors and NLRP3-related diseases, and explore new target for afatinib in macrophage.