Activation of AIM2 inflammasome cascade by extracellular trap-laden neutrophil vesicles triggered by Fusobacterium nucleatum exacerbates ulcerative colitis

Neutrophil dysfunction and activation of the absent in melanoma 2 (AIM2) inflammasome have been implicated in ulcerative colitis (UC) pathogenesis. However, whether these two immune responses interact synergistically and their precise role in UC remains unclear. Here, we performed bioinformatics and clinical analyses to assess neutrophil extracellular traps (NETs) and AIM2 inflammasome cascades in UC, including their correlation. Dual immunofluorescence revealed the predominant cell types expressing AIM2. Neutrophil activation and NETs release were examined in Fusobacterium nucleatum ( Fn )-stimulated cell models, while in vitro and in vivo studies investigated the effect of NETs on AIM2 inflammasome activation, UC severity, and therapeutic potential. Bioinformatics revealed co-up-regulation and significant co-expression of AIM2 inflammasome cascade-related genes and NETs-related genes in active UC. Confocal imaging showed that AIM2 primarily localized to intestinal epithelial cells in intestinal biopsies from UC patients and colon tissues from UC model mice. Fn infection partially promoted neutrophil activation and the release of NETs via neutrophil extracellular vesicles (nEVs). NETs were carried by nEVs and internalized by intestinal epithelial cells, subsequently triggering AIM2 inflammasome-dependent pyroptosis. In vivo studies demonstrated that elevated AIM2 inflammasome-related indicators triggered by Fn -stimulated nEVs-NETs were related to UC severity. Therapeutically, blockade of the nEVs-NETs/AIM2 inflammasome cascade using the NET-degrading agent DNase I or the AIM2 inhibitor A151 effectively attenuated colitis. Collectively, AIM2 inflammasome cascade activation by NETs-laden nEVs triggered by Fn exacerbates ulcerative colitis, highlighting the nEVs-NETs/AIM2 inflammasome cascade as a promising therapeutic target.