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

Ochratoxin 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, an...

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Autores principales:	Kai Liu, Dongmei Yue, Xinru Mao, Hu Li, Jie Qu, Shuiping Liu, Viktor I. Korolchuk, Yunhuan Liu, Fang Gan, Cuiling Pan, Kehe Huang, Xingxiang Chen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Ochratoxin A Pyroptosis Autophagy Reactive Oxidative stress NLRP3 inflammasome Environmental pollution TD172-193.5 Environmental sciences GE1-350
Acceso en línea:	https://doaj.org/article/7afbedaff66f44c0a7ad47744c03c267
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spelling	oai:doaj.org-article:7afbedaff66f44c0a7ad47744c03c2672021-12-04T04:32:05ZOchratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro0147-651310.1016/j.ecoenv.2021.113050https://doaj.org/article/7afbedaff66f44c0a7ad47744c03c2672021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0147651321011623https://doaj.org/toc/0147-6513Ochratoxin 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.Kai LiuDongmei YueXinru MaoHu LiJie QuShuiping LiuViktor I. KorolchukYunhuan LiuFang GanCuiling PanKehe HuangXingxiang ChenElsevierarticleOchratoxin APyroptosisAutophagyReactive Oxidative stressNLRP3 inflammasomeEnvironmental pollutionTD172-193.5Environmental sciencesGE1-350ENEcotoxicology and Environmental Safety, Vol 228, Iss , Pp 113050- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ochratoxin A Pyroptosis Autophagy Reactive Oxidative stress NLRP3 inflammasome Environmental pollution TD172-193.5 Environmental sciences GE1-350
spellingShingle	Ochratoxin A Pyroptosis Autophagy Reactive Oxidative stress NLRP3 inflammasome Environmental pollution TD172-193.5 Environmental sciences GE1-350 Kai Liu Dongmei Yue Xinru Mao Hu Li Jie Qu Shuiping Liu Viktor I. Korolchuk Yunhuan Liu Fang Gan Cuiling Pan Kehe Huang Xingxiang Chen Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro
description	Ochratoxin 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.
format	article
author	Kai Liu Dongmei Yue Xinru Mao Hu Li Jie Qu Shuiping Liu Viktor I. Korolchuk Yunhuan Liu Fang Gan Cuiling Pan Kehe Huang Xingxiang Chen
author_facet	Kai Liu Dongmei Yue Xinru Mao Hu Li Jie Qu Shuiping Liu Viktor I. Korolchuk Yunhuan Liu Fang Gan Cuiling Pan Kehe Huang Xingxiang Chen
author_sort	Kai Liu
title	Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro
title_short	Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro
title_full	Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro
title_fullStr	Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro
title_full_unstemmed	Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro
title_sort	ochratoxin a induces nlrp3 inflammasome-mediated pyroptosis via activation of ros modulated by autophagy in vitro
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/7afbedaff66f44c0a7ad47744c03c267
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Ochratoxin A induces NLRP3 inflammasome-mediated pyroptosis via activation of ROS modulated by autophagy in vitro

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