Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2024; 30(3): 252-267
Published online Jan 21, 2024. doi: 10.3748/wjg.v30.i3.252
SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis
Qing Gu, Huan Xia, Yue-Qiong Song, Jun Duan, Yun Chen, You Zhang, He-Ping Chen, Li Zhang
Qing Gu, Yue-Qiong Song, Jun Duan, Yun Chen, You Zhang, He-Ping Chen, Li Zhang, Department of Elderly Digestive, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology, Chengdu 610072, Sichuan Province, China
Huan Xia, He-Ping Chen, Li Zhang, Geriatrics Research Institute, Sichuan Provincial People’s Hospital, Chengdu 610072, Sichuan Province, China
Co-first authors: Qing Gu and Huan Xia.
Co-corresponding authors: He-Ping Chen and Li Zhang.
Author contributions: Gu Q and Xia H contributed equally to this work; Chen HP and Zhang L conceived and designed the study and provided administrative support; Gu Q, Xia H and Zhang L performed the experiments and analyzed data; Gu Q, Song YQ, Duan J and Chen HP analyzed and interpreted the data; Xia H, Chen Y, Zhang Y and Zhang L wrote the manuscript; all authors read and approved the final manuscript.
Supported by The Key Research and Development Projects of Sichuan Science and Technology Department, No. 2023YFS0285; and Natural Science Foundation Project of Sichuan Science and Technology Department, No. 2023NSFSC0613.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital.
Institutional animal care and use committee statement: All animal experiments were performed following the approval of the Animal Care and Use Committee of Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital [Lunshen (Yan)2022-380].
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Li Zhang, PhD, Doctor, Professor, Department of Elderly Digestive, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology, 32 West Section 2, Yihuan Road, Chengdu 610072, Sichuan Province, China. 1262867096@qq.com
Received: August 31, 2023
Peer-review started: August 31, 2023
First decision: October 29, 2023
Revised: November 8, 2023
Accepted: December 18, 2023
Article in press: December 18, 2023
Published online: January 21, 2024
Processing time: 139 Days and 20 Hours
Abstract
BACKGROUND

Ulcerative colitis (UC) is an inflammatory condition with frequent relapse and recurrence. Evidence suggests the involvement of SLC6A14 in UC pathogenesis, but the central regulator remains unknown.

AIM

To explore the role of SLC6A14 in UC-associated pyroptosis.

METHODS

Quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, and immunohistochemical were used to assess SLC6A14 in human UC tissues. Lipopolysaccharide (LPS) was used to induce inflammation in FHC and NCM460 cells and model enteritis, and SLC6A14 levels were assessed. Pyroptosis markers were quantified using enzyme-linked immunosorbent assay, Western blotting, and qRT-PCR, and EdU incubation, CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis. Mouse models of UC were used for verification.

RESULTS

SLC6A14 was increased and correlated with NLRP3 in UC tissues. LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels. Reducing SLC6A14 increased cell proliferation and suppressed apoptosis. Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β, IL-18, NLRP3). NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis. SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis.

CONCLUSION

SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.

Keywords: Ulcerative colitis; SLC6A1; NLRP3; Pyroptosis; Inflammasome

Core Tip: Ulcerative colitis (UC) is an inflammatory condition associated with frequent relapse and recurrence. Dysregulation of intestinal epithelial cells (IECs) and mucosal barrier impairment contribute to sustained inflammation in UC. Hence, an in-depth exploration of the triggers and mechanisms of IEC death could result in efficacious therapeutic options for UC patients. Here, we demonstrated the close involvement of SLC6A14 in promoting pyroptosis in the context of UC by upregulating NLRP3 expression. These findings indicate the potential of targeting SLC6A14/NLRP3 axis-mediated pyroptosis as a promising therapeutic strategy for treating UC. Our research provides valuable insights into the mechanisms driving UC pathogenesis and offers a possible direction for developing innovative treatments to alleviate the impact of this chronic inflammatory disorder.