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TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice
BACKGROUND: Anxiety and depression-like behaviors in allergic rhinitis (AR) are attracting attention, while the precise mechanism has not been clearly elucidated. Recent evidence shows that neuroinflammation in anterior cingulate cortex (ACC) may be the core of these neuropsychiatric symptoms in AR....
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680276/ https://www.ncbi.nlm.nih.gov/pubmed/38012545 http://dx.doi.org/10.1186/s10020-023-00757-9 |
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author | Gao, Ziang Lv, Hao Wang, Yunfei Xie, Yulie Guan, Mengting Xu, Yu |
author_facet | Gao, Ziang Lv, Hao Wang, Yunfei Xie, Yulie Guan, Mengting Xu, Yu |
author_sort | Gao, Ziang |
collection | PubMed |
description | BACKGROUND: Anxiety and depression-like behaviors in allergic rhinitis (AR) are attracting attention, while the precise mechanism has not been clearly elucidated. Recent evidence shows that neuroinflammation in anterior cingulate cortex (ACC) may be the core of these neuropsychiatric symptoms in AR. Here, we investigated the molecular link between the anxiety and depression-like behaviors and neuroinflammation in ACC. METHODS: Mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Nasal inflammation levels were assessed by H&E staining and PAS staining. Anxiety and depression-like behaviors were evaluated by behavioral experiments including open field test, forced swimming test, and sucrose preference test. Neuronal impairment was characterized via Nissl staining and (18)FDG-PET. The role of ten-eleven translocation 2 (TET2) in AR-related anxiety and depression was assessed by Tet2−/− mice. In addition, the murine BV2 microglial cell line was utilized to explore the molecular mechanisms by which TET2 mediates neuroinflammation. The levels of TET2, NLRP3 and their downstream molecules were detected by immunohistochemistry, Western blot, Dot blot and ELISA. The effects of metformin on depression-like behaviors in AR mice were also evaluated. RESULTS: AR mice showed significant anxiety and depression-like behaviors, which associated with the activation of ACC. Loss of TET2 activated the NLRP3/IL-1β pathway of microglia in AR mice, further accelerating the anxiety and depression-like behaviors. In addition, knockdown of TET2 activated the NLRP3/IL-1β pathway in BV2 cells. Metformin improved the neuropsychiatric symptoms of AR mice by reducing the activation of NLRP3/IL-1β pathway after upregulating TET2. CONCLUSION: TET2 deficiency activates the NLRP3/IL-1β pathway of microglia in the ACC, promoting the pathological process of anxiety and depression-like behavior in AR. Metformin could be effective in treating neuroinflammation by regulating microglia via TET2 up-regulation, indicating that metformin is a potential way to treat anxiety and depression-like behaviors in AR. |
format | Online Article Text |
id | pubmed-10680276 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106802762023-11-27 TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice Gao, Ziang Lv, Hao Wang, Yunfei Xie, Yulie Guan, Mengting Xu, Yu Mol Med Research Article BACKGROUND: Anxiety and depression-like behaviors in allergic rhinitis (AR) are attracting attention, while the precise mechanism has not been clearly elucidated. Recent evidence shows that neuroinflammation in anterior cingulate cortex (ACC) may be the core of these neuropsychiatric symptoms in AR. Here, we investigated the molecular link between the anxiety and depression-like behaviors and neuroinflammation in ACC. METHODS: Mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Nasal inflammation levels were assessed by H&E staining and PAS staining. Anxiety and depression-like behaviors were evaluated by behavioral experiments including open field test, forced swimming test, and sucrose preference test. Neuronal impairment was characterized via Nissl staining and (18)FDG-PET. The role of ten-eleven translocation 2 (TET2) in AR-related anxiety and depression was assessed by Tet2−/− mice. In addition, the murine BV2 microglial cell line was utilized to explore the molecular mechanisms by which TET2 mediates neuroinflammation. The levels of TET2, NLRP3 and their downstream molecules were detected by immunohistochemistry, Western blot, Dot blot and ELISA. The effects of metformin on depression-like behaviors in AR mice were also evaluated. RESULTS: AR mice showed significant anxiety and depression-like behaviors, which associated with the activation of ACC. Loss of TET2 activated the NLRP3/IL-1β pathway of microglia in AR mice, further accelerating the anxiety and depression-like behaviors. In addition, knockdown of TET2 activated the NLRP3/IL-1β pathway in BV2 cells. Metformin improved the neuropsychiatric symptoms of AR mice by reducing the activation of NLRP3/IL-1β pathway after upregulating TET2. CONCLUSION: TET2 deficiency activates the NLRP3/IL-1β pathway of microglia in the ACC, promoting the pathological process of anxiety and depression-like behavior in AR. Metformin could be effective in treating neuroinflammation by regulating microglia via TET2 up-regulation, indicating that metformin is a potential way to treat anxiety and depression-like behaviors in AR. BioMed Central 2023-11-27 /pmc/articles/PMC10680276/ /pubmed/38012545 http://dx.doi.org/10.1186/s10020-023-00757-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Gao, Ziang Lv, Hao Wang, Yunfei Xie, Yulie Guan, Mengting Xu, Yu TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice |
title | TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice |
title_full | TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice |
title_fullStr | TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice |
title_full_unstemmed | TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice |
title_short | TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice |
title_sort | tet2 deficiency promotes anxiety and depression-like behaviors by activating nlrp3/il-1β pathway in microglia of allergic rhinitis mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680276/ https://www.ncbi.nlm.nih.gov/pubmed/38012545 http://dx.doi.org/10.1186/s10020-023-00757-9 |
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