College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China.
Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China.
Int J Mol Sci. 2023 Jul 14;24(14):11451. doi: 10.3390/ijms241411451.
The high-pathogenicity island (HPI) was initially identified in Yersinia and can be horizontally transferred to to produce yersiniabactin (Ybt), which enhances the pathogenicity of by competing with the host for Fe. Pyroptosis is gasdermin-induced necrotic cell death. It involves the permeabilization of the cell membrane and is accompanied by an inflammatory response. It is still unclear whether Ybt HPI can cause intestinal epithelial cells to undergo pyroptosis and contribute to gut inflammation during infection. In this study, we infected intestinal epithelial cells of mice with ZB-1 and the Ybt-deficient strain ZB-1Δ. Our findings demonstrate that Ybt-producing is more toxic and exacerbates gut inflammation during systemic infection. Mechanistically, our results suggest the involvement of the NLRP3/caspase-1/GSDMD pathway in infection. Ybt promotes the assembly and activation of the NLRP3 inflammasome, leading to GSDMD cleavage into GSDMD-N and promoting the pyroptosis of intestinal epithelial cells, ultimately aggravating gut inflammation. Notably, NLRP3 knockdown alleviated these phenomena, and the binding of free Ybt to NLRP3 may be the trigger. Overall, our results show that Ybt HPI enhances the pathogenicity of and induces pyroptosis via the NLRP3 pathway, which is a new mechanism through which promotes gut inflammation. Furthermore, we screened drugs targeting NLRP3 from an existing drug library, providing a list of potential drug candidates for the treatment of gut injury caused by .
高致病性岛（HPI）最初在耶尔森氏菌中被发现，可以水平转移到 中产生耶尔森菌素（Ybt），通过与宿主竞争 Fe 来增强 的致病性。细胞焦亡是一种由gasdermin 诱导的坏死性细胞死亡。它涉及细胞膜的通透性，并伴随着炎症反应。目前尚不清楚 Ybt HPI 是否会导致肠上皮细胞发生细胞焦亡，并有助于 感染期间的肠道炎症。在这项研究中，我们用 ZB-1 和缺乏 Ybt 的菌株 ZB-1Δ 感染了小鼠的肠上皮细胞。我们的研究结果表明，产生 Ybt 的 毒性更强，在全身感染期间加剧肠道炎症。从机制上讲，我们的结果表明 NLRP3/caspase-1/GSDMD 途径参与了 感染。Ybt 促进 NLRP3 炎性小体的组装和激活，导致 GSDMD 切割成 GSDMD-N，并促进肠上皮细胞的细胞焦亡，最终加重肠道炎症。值得注意的是，NLRP3 的敲低减轻了这些现象，而游离 Ybt 与 NLRP3 的结合可能是触发因素。总的来说，我们的研究结果表明，Ybt HPI 通过 NLRP3 途径增强了 的致病性并诱导了细胞焦亡，这是 促进肠道炎症的新机制。此外，我们从现有的药物库中筛选出针对 NLRP3 的药物，为治疗 引起的肠道损伤提供了一系列潜在的药物候选物。
