Mst1/2-ALK promotes NLRP3 inflammasome activation and cell apoptosis during Listeria monocytogenes infection
Mst1/2-ALK promotes NLRP3 inflammasome activation and cell apoptosis during Listeria monocytogenes infection
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Mst1/2-ALK 在单核细胞增生李斯特菌感染过程中促进 NLRP3 炎性体激活和细胞凋亡
DOI：
10.1007/s12275-021-0638-2
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发表时间：
2021-04-20
影响因子：
3
通讯作者：
Shen, Yanna
中科院分区：
文献类型：
--
作者：
Gao, Aijiao;Tang, Huixin;Shen, Yanna
单核增生李斯特菌（L. monocytogenes）是一种革兰氏阳性的细胞内食源性病原体，可引起严重疾病，如脑膜炎和败血症。NLR家族pyrin - domain-containing 3 （NLRP3）炎性小体已被报道参与宿主防御病原体感染。然而，NLRP3炎性体激活的确切分子机制仍有待完全阐明。本研究探讨了哺乳动物ste20样激酶1/2 （Mst1/2）和间变性淋巴瘤激酶（ALK）在单核细胞增生乳杆菌感染诱导的NLRP3炎性体活化中的作用。单核细胞原乳杆菌感染巨噬细胞后，Mst1/2、phospho (p)-ALK、p- jnk、Nek7和NLRP3下游分子包括活化的caspase -1 （p20）和成熟的白细胞介素(IL)-1β (p17)的表达水平上调。ALK抑制剂显著降低单核增生乳杆菌感染巨噬细胞中p-JNK、Nek7和NLRP3下游分子的表达。此外，Mst1/2抑制剂显著抑制L. monocytogenes诱导的ALK活化，随后下调p-JNK、Nek7和NLRP3下游分子的表达。因此，我们的研究表明，Mst1/2-ALK在单核增生乳杆菌感染过程中通过JNK促进Nek7和NLRP3的相互作用，从而促进促炎细胞因子的成熟和释放，从而介导NLRP3炎性小体的活化，从而抵抗病原体感染。此外，李斯特菌素O在这一过程中发挥了关键作用。此外，我们还发现Mst1/2或ALK抑制剂可减少L. monocytogenes诱导的J774A.1细胞的凋亡。本研究首次报道了Mst1/2-ALK-JNK-NLRP3信号通路在单核增生乳杆菌感染过程中起重要的促炎作用。
Listeria monocytogenes (L. monocytogenes) is a Gram-positive intracellular foodborne pathogen that causes severe diseases, such as meningitis and sepsis. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been reported to participate in host defense against pathogen infection. However, the exact molecular mechanisms underlying NLRP3 inflammasome activation remain to be fully elucidated. In the present study, the roles of mammalian Ste20-like kinases 1/2 (Mst1/2) and Anaplastic Lymphoma Kinase (ALK) in the activation of the NLRP3 inflammasome induced by L. monocytogenes infection were investigated. The expression levels of Mst1/2, phospho (p)-ALK, p-JNK, Nek7, and NLRP3 downstream molecules including activated cas-pase-1 (p20) and mature interleukin (IL)-1β (p17), were up-regulated in L. monocytogenes-infected macrophages. The ALK inhibitor significantly decreased the expression of p-JNK, Nek7, and NLRP3 downstream molecules in macrophages infected with L. monocytogenes. Furthermore, the Mst1/2 inhibitor markedly inhibited the L. monocytogenes-induced activation of ALK, subsequently downregulating the expression of p-JNK, Nek7, and NLRP3 downstream molecules. Therefore, our study demonstrated that Mst1/2-ALK mediated the activation of the NLRP3 inflammasome by promoting the interaction between Nek7 and NLRP3 via JNK during L. monocytogenes infection, which subsequently increased the maturation and release of proinflammatory cytokine to resist pathogen infection. Moreover, Listeriolysin O played a key role in the process. In addition, we also found that the L. monocytogenes-induced apoptosis of J774A.1 cells was reduced by the Mst1/2 or ALK inhibitor. The present study reported, for the first time, that the Mst1/2-ALK-JNK-NLRP3 signaling pathway plays a vital proinflammatory role during L. monocytogenes infection.