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

  • Sci Rep. 2021 May 10;11(1):9832. doi: 10.1038/s41598-021-89210-7.
Takashi Toyama  1  2 ,  Takayuki Hoshi  1  2  3 ,  Takuya Noguchi  4 ,  Yoshiro Saito  2 ,  Atsushi Matsuzawa  4 ,  Akira Naganuma  1 ,  Gi-Wook Hwang  5  6
Affiliations
  • 1. Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan.
  • 2. Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
  • 3. Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.
  • 4. Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan.
  • 5. Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan. [email protected].
  • 6. Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan. [email protected].
PMID: 33972601 DOI: 10.1038/s41598-021-89210-7
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.

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