Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia

Abstract We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing...

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Autores principales:	Takashi Toyama, Takayuki Hoshi, Takuya Noguchi, Yoshiro Saito, Atsushi Matsuzawa, Akira Naganuma, Gi-Wook Hwang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aca787f298bc4591813bd5c3c424b4f7
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spelling	oai:doaj.org-article:aca787f298bc4591813bd5c3c424b4f72021-12-02T14:35:47ZMethylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia10.1038/s41598-021-89210-72045-2322https://doaj.org/article/aca787f298bc4591813bd5c3c424b4f72021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89210-7https://doaj.org/toc/2045-2322Abstract We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.Takashi ToyamaTakayuki HoshiTakuya NoguchiYoshiro SaitoAtsushi MatsuzawaAkira NaganumaGi-Wook HwangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takashi Toyama Takayuki Hoshi Takuya Noguchi Yoshiro Saito Atsushi Matsuzawa Akira Naganuma Gi-Wook Hwang Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia
description	Abstract We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.
format	article
author	Takashi Toyama Takayuki Hoshi Takuya Noguchi Yoshiro Saito Atsushi Matsuzawa Akira Naganuma Gi-Wook Hwang
author_facet	Takashi Toyama Takayuki Hoshi Takuya Noguchi Yoshiro Saito Atsushi Matsuzawa Akira Naganuma Gi-Wook Hwang
author_sort	Takashi Toyama
title	Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia
title_short	Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia
title_full	Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia
title_fullStr	Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia
title_full_unstemmed	Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia
title_sort	methylmercury induces neuronal cell death by inducing tnf-α expression through the ask1/p38 signaling pathway in microglia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/aca787f298bc4591813bd5c3c424b4f7
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_version_	1718391092213186560

Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia

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