Department of Stomatology, Nanfang Hospital, Southern Medical Universitygrid.284723.8, Guangzhou, China.
Stomatology Hospital, Southern Medical Universitygrid.284723.8, Guangzhou, China.
Microbiol Spectr. 2022 Aug 31;10(4):e0104522. doi: 10.1128/spectrum.01045-22. Epub 2022 Jun 16.
The persistence of residual bacteria, particularly Enterococcus faecalis, contributes to refractory periapical periodontitis, which still lacks effective therapy. The role of receptor-interacting protein kinase 3 (RIPK3)- and mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis, a highly proinflammatory form of regulated cell death, has recently drawn much attention. However, the role of necroptosis in the pathogenesis of refractory periapical periodontitis remains unclear. We investigated whether the RIPK3/MLKL signaling pathway was activated in periapical lesion specimens obtained from patients diagnosed with refractory periapical periodontitis. -deficient mice were then used to determine the role of necroptosis under this condition . We found that the phosphorylation levels of RIPK3 and MLKL were elevated in periapical lesion specimens of patients with refractory periapical periodontitis. In addition, necroptosis was induced in an E. faecalis-infected refractory periapical periodontitis mouse model, in which inhibition of necroptosis by RIPK3 deficiency could markedly alleviate inflammation and bone destruction. Moreover, double-labeling immunofluorescence suggested that macrophage necroptosis may be involved in the development of refractory periapical periodontitis. Then, we established an macrophage infection model with E. faecalis. E. faecalis infection was found to induce necroptotic cell death in macrophages through the RIPK3/MLKL signaling pathway, which was markedly alleviated by the RIPK3- or MLKL-specific inhibitor. Our study revealed that RIPK3/MLKL-mediated macrophage necroptosis contributes to the development of refractory periapical periodontitis and suggests that inhibitors or treatments targeting necroptosis represent a plausible strategy for the management of refractory periapical periodontitis. Oral infectious diseases represent a major neglected global population health challenge, imposing an increasing burden on public health and economy. Refractory apical periodontitis (RAP), mainly caused by Enterococcus faecalis, is a representative oral infectious disease with considerable therapeutic challenges. The interplay between E. faecalis and the host often leads to the activation of programmed cell death. This study identifies an important role of macrophage necroptosis induced by E. faecalis in the pathogenesis of RAP. Manipulating RIPK3/MLKL-mediated necroptosis may represent novel therapeutic targets, not only for RAP but also for other E. faecalis-associated infectious diseases.
残留细菌（尤其是粪肠球菌）的持续存在是导致难治性根尖周炎的原因之一，而目前这种疾病仍然缺乏有效的治疗方法。受体相互作用蛋白激酶 3（RIPK3）-和混合谱系激酶结构域样蛋白（MLKL）介导的细胞坏死，一种高度促炎的调控性细胞死亡形式，最近引起了广泛关注。然而，细胞坏死在难治性根尖周炎发病机制中的作用尚不清楚。本研究旨在探讨 RIPK3/MLKL 信号通路是否在患有难治性根尖周炎患者的根尖病变标本中被激活。然后使用 RIPK3 缺陷型小鼠来确定在这种情况下细胞坏死的作用。结果发现，难治性根尖周炎患者的根尖病变标本中 RIPK3 和 MLKL 的磷酸化水平升高。此外，在粪肠球菌感染的难治性根尖周炎小鼠模型中诱导了细胞坏死，而 RIPK3 缺陷抑制细胞坏死可显著减轻炎症和骨破坏。此外，双标记免疫荧光提示巨噬细胞坏死可能参与难治性根尖周炎的发生。然后，我们建立了一个用粪肠球菌感染的巨噬细胞模型。研究发现，粪肠球菌感染通过 RIPK3/MLKL 信号通路诱导巨噬细胞发生坏死性细胞死亡，而 RIPK3 或 MLKL 的特异性抑制剂可显著减轻这种作用。本研究揭示了 RIPK3/MLKL 介导的巨噬细胞坏死参与了难治性根尖周炎的发生发展，并提示针对细胞坏死的抑制剂或治疗方法可能是治疗难治性根尖周炎的一种可行策略。口腔感染性疾病是全球重大的被忽视的人群健康挑战之一，给公共卫生和经济带来了越来越大的负担。难治性根尖周炎（RAP）主要由粪肠球菌引起，是一种具有相当治疗挑战的代表性口腔感染性疾病。粪肠球菌与宿主之间的相互作用常常导致程序性细胞死亡的激活。本研究鉴定出粪肠球菌诱导的巨噬细胞坏死在 RAP 发病机制中的重要作用。操纵 RIPK3/MLKL 介导的坏死可能代表一种新的治疗靶点，不仅针对 RAP，还针对其他与粪肠球菌相关的感染性疾病。
