Shenker Bruce J, Korostoff Jonathan, Walker Lisa P, Zekavat Ali, Dhingra Anuradha, Kim Taewan J, Boesze-Battaglia Kathleen
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Pathogens. 2024 Feb 8;13(2):155. doi: 10.3390/pathogens13020155.
Recently, we reported that oral-epithelial cells (OE) are unique in their response to cytolethal distending toxin (Cdt) in that cell cycle arrest (G2/M) occurs without leading to apoptosis. We now demonstrate that Cdt-induced cell cycle arrest in OE has a duration of at least 7 days with no change in viability. Moreover, toxin-treated OE develops a new phenotype consistent with cellular senescence; this includes increased senescence-associated β-galactosidase (SA-β-gal) activity and accumulation of the lipopigment, lipofuscin. Moreover, the cells exhibit a secretory profile associated with cellular senescence known as the senescence-associated secretory phenotype (SASP), which includes IL-6, IL-8 and RANKL. Another unique feature of Cdt-induced OE senescence is disruption of barrier function, as shown by loss of transepithelial electrical resistance and confocal microscopic assessment of primary gingival keratinocyte structure. Finally, we demonstrate that Cdt-induced senescence is dependent upon the host cell protein cellugyrin, a homologue of the synaptic vesicle protein synaptogyrin. Collectively, these observations point to a novel pathogenic outcome in oral epithelium that we propose contributes to both infection and periodontal disease progression.
最近，我们报道口腔上皮细胞（OE）对细胞致死性扩张毒素（Cdt）的反应具有独特性，即细胞周期停滞在G2/M期，且不会导致细胞凋亡。我们现在证明，Cdt诱导的OE细胞周期停滞持续至少7天，细胞活力无变化。此外，经毒素处理的OE呈现出与细胞衰老一致的新表型；这包括衰老相关β-半乳糖苷酶（SA-β-gal）活性增加以及脂褐素（一种脂色素）的积累。此外，这些细胞表现出与细胞衰老相关的分泌谱，即衰老相关分泌表型（SASP），其中包括白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和核因子κB受体活化因子配体（RANKL）。Cdt诱导的OE衰老的另一个独特特征是屏障功能的破坏，这表现为跨上皮电阻的丧失以及对原代牙龈角质形成细胞结构的共聚焦显微镜评估。最后，我们证明Cdt诱导的衰老依赖于宿主细胞蛋白细胞动蛋白，它是突触小泡蛋白突触动蛋白的同源物。总的来说，这些观察结果表明口腔上皮中存在一种新的致病结果，我们认为这对感染和牙周病进展都有影响。
