Hypoxia-induced NLRP3 inflammasome activation via the HIF-1α/NF-κB signaling pathway in human dental pulp fibroblasts

Wang, Diya, Wang, Minghao, Sun, Shukai, Zhang, Chongyang, Song, Ya, Li, Jianing, Song, Bing ORCID: https://orcid.org/0000-0001-9356-2333, Lv, Haipeng, Wang, Shengchao and Jiang, Wenkai 2024. Hypoxia-induced NLRP3 inflammasome activation via the HIF-1α/NF-κB signaling pathway in human dental pulp fibroblasts. BMC Oral Health 24 (1) , 1156. 10.1186/s12903-024-04936-w

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Dentistry
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	BioMed Central
Date of First Compliant Deposit:	30 September 2024
Date of Acceptance:	19 September 2024
Last Modified:	30 Sep 2024 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/172469

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