Hu Yajie, Deng Xiaoli, Lv Yaming, Liu Chen, Chen Juan, Song Jie, Zhang Yunhui
Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
National & Local Engineering Center for Infectious Biological Products, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China.
Mol Immunol. 2025 Feb;178:107-116. doi: 10.1016/j.molimm.2025.01.012. Epub 2025 Jan 30.
Neuronal death and neuroinflammation has been considered as the main contributors to the progression and deterioration of HFMD caused by CV-A10. Necroptosis is a lytic and inflammatory form of cell death that plays a crucial role in viral pathogenicity. Herein, our study showed that CV-A10-infected SH-SY5Y cells induced necroptosis via activating RIPK3-depedent pathway, but not requiring RIPK1, and meanwhile triggered the release of inflammatory cytokines. Moreover, RIPK3-mediated necroptosis was also involved in virus production, which did not require RIPK1 either. Finally, it was further verified that TLR3 drove RIPK3-mediated cell death by sensing CV-A10 RNA and activating RIPK3. Collectively, our study demonstrated that initiation of necroptosis in SH-SY5Y cells induced by CV-A10 accelerated the formation of inflammatory response and promoted virus replication through triggering a TLR3-initiated RIPK3-dependent pathway of necroptosis, which advanced the current understanding of necroptosis for the neuropathogenesis of CV-A10 infection.
神经元死亡和神经炎症被认为是导致由A10型柯萨奇病毒（CV-A10）引起的手足口病进展和恶化的主要因素。坏死性凋亡是一种细胞死亡的溶解性和炎症性形式，在病毒致病性中起关键作用。在此，我们的研究表明，CV-A10感染的SH-SY5Y细胞通过激活依赖于受体相互作用蛋白激酶3（RIPK3）的途径诱导坏死性凋亡，但不需要RIPK1，同时触发炎症细胞因子的释放。此外，RIPK3介导的坏死性凋亡也参与病毒产生，这也不需要RIPK1。最后，进一步证实Toll样受体3（TLR3）通过感知CV-A10 RNA并激活RIPK3来驱动RIPK3介导的细胞死亡。总体而言，我们的研究表明，CV-A10诱导的SH-SY5Y细胞中坏死性凋亡的启动通过触发由TLR3启动的RIPK3依赖性坏死性凋亡途径加速炎症反应的形成并促进病毒复制，这推进了目前对坏死性凋亡在CV-A10感染神经发病机制中的理解。
