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Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro

Lookup NU author(s): Dr Viktor Korolchuk

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2021 The AuthorsOchratoxin A (OTA), one of the major food contaminating mycotoxins, has been reported to cause renal fibrosis through pyroptosis, but the detailed mechanism of its nephrotoxicity remains to be further investigated. Autophagy can be seen in the physiological and pathological processes of the body, and whether its role is positive or negative has not been fully elucidated. The aim of this paper was to explore the role of autophagic-inflammasomal pathway on pyroptosis caused by low levels of OTA in vitro. The results showed that OTA dose-dependently decreased cell viability in PK-15 cells and the half-maximal inhibitory concentration (IC50) was 5.9 µM. OTA could significantly increase pro-inflammatory cytokines (TNF-α, IL-1β, IL-18, IL-6) expression, induced pyroptosis and NLRP3 inflammasome formation at 1.0–4.0 µM for 48 h according to the results of qPCR, Western blotting, Immunofluorescence staining and morphologic observation. But MCC950 (an inhibitor of NLRP3) treatment or caspase-1 (sicaspase-1) knockdown could restore these changes. Additionally, we further found that reactive oxygen species (ROS) contributed to OTA-induced NLRP3 inflammasome and pyroptosis in PK-15 cells as indicated by Western blotting and immunofluorescence. Besides, we indicated that OTA induced autophagy via AKT/mTOR signaling pathway. And 3-MA (an inhibitor of autophagy) treatment or ATG5 (siATG5) knockdown enhanced ROS levels and NLRP3 inflammasome formation exposed to OTA. Taken together, our results elaborated that ROS/NLRP3-inlflammasome-mediated pyroptosis could be involved in the low levels of OTA-induced nephrotoxicity, which was negatively regulated by autophagy.


Publication metadata

Author(s): Liu K, Yue D, Mao X, Li H, Qu J, Liu S, Korolchuk VI, Liu Y, Gan F, Pan C, Huang K, Chen X

Publication type: Article

Publication status: Published

Journal: Ecotoxicology and Environmental Safety

Year: 2021

Volume: 228

Print publication date: 25/12/2021

Online publication date: 03/12/2021

Acceptance date: 30/11/2021

Date deposited: 16/12/2021

ISSN (print): 0147-6513

ISSN (electronic): 1090-2414

Publisher: Academic Press

URL: https://doi.org/10.1016/j.ecoenv.2021.113050

DOI: 10.1016/j.ecoenv.2021.113050


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Funding

Funder referenceFunder name
National Natural Science Foundation of China (NSFC) (31972745, 31811530300),
MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University.
Priority Program Development of Jiangsu Higher Education Institutions (Jiangsu, China),

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