Xie Jia-Wen, Guo Yin-Feng, Fan Shu-Hao, Zheng Ying, Zhang Hui-Lin, Zhang Yan, Zhang Yi, Lin Li-Rong
Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China.
Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Int J Biol Macromol. 2024 Dec;283(Pt 4):137991. doi: 10.1016/j.ijbiomac.2024.137991. Epub 2024 Nov 22.
Syphilis is a sexually transmitted disease caused by Treponema pallidum. The mechanisms enabling T. pallidum to persist despite macrophage eradication efforts in syphilis remain unclear. Pathogens can exploit senescent cells to enhance host susceptibility, and cellular senescence can be induced by pyroptosis, which known as inflammatory senescence. While recent studies have linked metabolic reprogramming to inflammatory senescence, their role in syphilis remained to be clarified. This study investigated the mechanisms of Tp47 on metabolic reprogramming and inflammatory senescence in macrophages. The results demonstrated that Tp47 triggered NLRP3 inflammasome-mediated pyroptosis by activating the phosphorylation of EIF2AK2 (a protein kinase), increasing senescence-associated pro-inflammatory cytokines secretion and leading to inflammatory senescence in macrophages. Additionally, Tp47 competitively bound to pyruvate kinase M2 (PKM2) with STUB1(a ubiquitin ligase), thereby inhibiting PKM2 ubiquitination degradation. By promoting the Y105 phosphorylation of PKM2, Tp47 modulated the intracellular function of PKM2, and facilitated PKM2-mediated metabolic reprogramming, which produced lactate that subsequently led to EIF2AK2 phosphorylation. Furthermore, inhibitors targeting EIF2AK2, lactate, glycolysis, and PKM2 effectively suppressed the inflammatory senescence induced by Tp47. In conclusion, Tp47 could mediate immune metabolic reprogramming through interaction with PKM2 to trigger macrophage inflammatory senescence. These discoveries offer a novel perspective for targeted therapies against syphilis.
梅毒是一种由梅毒螺旋体引起的性传播疾病。尽管在梅毒治疗中巨噬细胞努力清除梅毒螺旋体，但梅毒螺旋体仍能持续存在的机制尚不清楚。病原体可以利用衰老细胞来增强宿主易感性，并且细胞衰老可由焦亡诱导，这被称为炎症性衰老。虽然最近的研究已将代谢重编程与炎症性衰老联系起来，但它们在梅毒中的作用仍有待阐明。本研究调查了Tp47对巨噬细胞代谢重编程和炎症性衰老的机制。结果表明，Tp47通过激活EIF2AK2（一种蛋白激酶）的磷酸化，触发NLRP3炎性小体介导的焦亡，增加衰老相关促炎细胞因子的分泌，并导致巨噬细胞炎症性衰老。此外，Tp47与STUB1（一种泛素连接酶）竞争性结合丙酮酸激酶M2（PKM2），从而抑制PKM2的泛素化降解。通过促进PKM2的Y105磷酸化，Tp47调节PKM2的细胞内功能，并促进PKM2介导的代谢重编程，产生乳酸，随后导致EIF2AK2磷酸化。此外，靶向EIF2AK2、乳酸、糖酵解和PKM2的抑制剂有效地抑制了Tp47诱导的炎症性衰老。总之，Tp47可通过与PKM2相互作用介导免疫代谢重编程，从而触发巨噬细胞炎症性衰老。这些发现为梅毒的靶向治疗提供了新的视角。
