缺氧诱导的人牙髓成纤维细胞中 NLRP3 炎性小体通过 HIF-1α/NF-κB 信号通路的激活。
Hypoxia-induced NLRP3 inflammasome activation via the HIF-1α/NF-κB signaling pathway in human dental pulp fibroblasts.
机构信息
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Operative Dentistry & Endodontics, School of Stomatology, Fourth Military Medical University, No.145 Western Changle Road, Xi'an, Shaanxi, 710032, China.
Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi, China.
出版信息
BMC Oral Health. 2024 Sep 29;24(1):1156. doi: 10.1186/s12903-024-04936-w.
BACKGROUND
Previous studies have reported the link between hypoxic conditions and NLRP3 inflammasome-mediated pulpal inflammation in the progression of pulpitis. However, the underlying mechanism has not been fully elucidated. This study aimed to investigate the role of HIF-1α in the regulation of NLRP3 inflammasome pathway via NF-κB signaling under hypoxic conditions with or without LPS in human dental pulp fibroblasts (HDPFs) during the progression of pulpitis.
METHODS
HIF-1α plasmids or siRNAs were used to upregulate or downregulate HIF-1α in HDPFs, respectively. The effect of hypoxia with or without LPS on the NF-κB signaling and NLRP3 inflammasome pathway was analyzed by immunofluorescence staining, qRT-PCR, western blotting and ELISA.
RESULTS
The hypoxic conditions alone induced ASC oligomerization and NLRP3/CASP1 inflammasome pathway activation via NF-κB signaling in a time-dependent manner in HDPFs. The upregulation of HIF-1α further promoted hypoxia-induced ASC oligomerization and NLRP3/CASP1 inflammasome pathway activation via NF-κB signaling compared to the hypoxia-induced group. In comparison, downregulation of HIF-1α inhibited ASC oligomerization and NLRP3/CASP1 inflammasome pathway activation via NF-κB signaling compared to the hypoxia-induced group. Additionally, LPS plus hypoxia further promoted HIF-1α expression and NLRP3/ASC/CASP1 inflammasome pathway activation via NF-κB signaling compared to the hypoxia-induced group.
CONCLUSIONS
HIF-1α served as a positive regulator of NLRP3/ASC/CASP1 inflammasome pathway activation via NF-κB signaling in HDPFs in the sterile pulpal inflammation and caries-related pulpitis microenvironment. The finding of a novel functional HIF-1α-NF-κB-NLRP3 axis provides insight into the link between the hypoxic microenvironment and pulpal inflammation, thus supporting a promising therapeutic strategy for the control of pulpal inflammation.
背景
先前的研究已经报道了缺氧条件与 NLRP3 炎性体介导体牙髓炎症在牙髓炎进展之间的联系。然而，其潜在机制尚未完全阐明。本研究旨在探讨在牙髓炎症进展过程中，缺氧条件下 LPS 对人牙髓成纤维细胞（HDPFs）中 NLRP3 炎性体通路的调节作用及其与 NF-κB 信号通路的关系。
方法
分别用 HIF-1α 质粒或 siRNA 上调或下调 HDPFs 中的 HIF-1α。通过免疫荧光染色、qRT-PCR、Western blot 和 ELISA 分析缺氧（有无 LPS）对 NF-κB 信号通路和 NLRP3 炎性体通路的影响。
结果
单纯缺氧条件下，HDPFs 中 ASC 寡聚化和 NLRP3/CASP1 炎性体通路激活呈时间依赖性，通过 NF-κB 信号通路激活。与缺氧诱导组相比，HIF-1α 的上调进一步促进了缺氧诱导的 ASC 寡聚化和 NLRP3/CASP1 炎性体通路激活，通过 NF-κB 信号通路。相比之下，与缺氧诱导组相比，HIF-1α 的下调抑制了 ASC 寡聚化和 NLRP3/CASP1 炎性体通路激活，通过 NF-κB 信号通路。此外，与缺氧诱导组相比，LPS 加缺氧进一步促进了 HIF-1α 的表达和 NLRP3/ASC/CASP1 炎性体通路激活，通过 NF-κB 信号通路。
结论
在无菌性牙髓炎症和龋相关牙髓炎症的微环境中，HIF-1α 作为 NF-κB 信号通路中 NLRP3/ASC/CASP1 炎性体通路激活的正调节剂。该研究发现了一个新的功能性 HIF-1α-NF-κB-NLRP3 轴，为缺氧微环境与牙髓炎症之间的联系提供了新的认识，为控制牙髓炎症提供了有前途的治疗策略。
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