Fusobacterium nucleatum-derived extracellular vesicles carrying virulence factor DNA trigger AIM2 inflammasome activation to facilitate UC progression
Yu-Qing Zhao, Rui Wu, Yaqian Duan, Xuehua Kong, Yuxin Zhang, Yan You, Jianbo Zhang, Yunying Wang, Lan Zhou, Liang Duan
Abstract
BACKGROUND: Immune disorders and impaired intestinal barrier function resulting from dysbiosis of the intestinal flora play pivotal roles in the pathogenesis of ulcerative colitis (UC). Fusobacterium nucleatum (F. nucleatum, Fn) can secrete extracellular vesicles (EVs) that surmount the mucus layer, thereby contributing to UC progression. However, the underlying mechanisms and their clinical significance remain elusive. METHODS: Bioinformatics and clinical sample analysis were employed to explore the relationship between F. nucleatum and the absent in melanoma 2 (AIM2) inflammasome. Both in vivo and in vitro studies were performed to analyze the regulatory effects of extracellular vesicles released by F. nucleatum (Fn-EVs), which carry harmful molecules to the AIM2 inflammasome, as well as their ultimate role and clinical significance in UC progression. RESULTS: Bioinformatics analysis showed upregulated expression of AIM2 and downstream pyroptosis-related genes in active UC, and that the AIM2 gene was linked to bacterial invasion and tight junctions. The clinical correlation between both F. nucleatum and its virulence proteins and the AIM2 inflammasome and downstream molecules was verified. Internalization of Fn-EVs by intestinal epithelial cells (IECs) triggered activation of the AIM2 inflammasome along with downstream pyroptosis molecules, resulting in damage to the intestinal barrier. Furthermore, we revealed that DNA components within Fn-EVs (Fn-EVs-DNA) play crucial roles in inducing these effects. Administration of DNase I, which targets Fn-EVs-DNA or A151 to block AIM2 inflammasome activation, effectively alleviated pyroptosis in IECs and restored gut barrier integrity, thereby mitigating UC progression. CONCLUSIONS: Fn-EVs carrying the virulence factor DNA (Fn-DNA) are internalized by IECs to trigger AIM2 inflammasome-dependent pyroptosis and intestinal barrier disruption, eventually aggravating colitis. Targeting the Fn-EVs-DNA–AIM2 cascade may represent a promising therapeutic strategy for UC.