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Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis
BACKGROUND: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a ke...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855604/ https://www.ncbi.nlm.nih.gov/pubmed/35180864 http://dx.doi.org/10.1186/s12974-022-02415-z |
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author | Zheng, Wu Feng, Yijia Zeng, Zhenhai Ye, Mengqian Wang, Mengru Liu, Xin Tang, Ping Shang, Huiping Sun, Xiaoting Lin, Xiangxiang Wang, Muran Li, Zhengzheng Weng, Yiyun Guo, Wei Vakal, Sergii Chen, Jiang-fan |
author_facet | Zheng, Wu Feng, Yijia Zeng, Zhenhai Ye, Mengqian Wang, Mengru Liu, Xin Tang, Ping Shang, Huiping Sun, Xiaoting Lin, Xiangxiang Wang, Muran Li, Zhengzheng Weng, Yiyun Guo, Wei Vakal, Sergii Chen, Jiang-fan |
author_sort | Zheng, Wu |
collection | PubMed |
description | BACKGROUND: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A(2A) receptor (A(2A)R) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A(2A)R-mediated protection remains undetermined. METHODS: In the EAE model, we assessed A(2A)R expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A(2A)R antagonist KW6002 treatment at days 8–12 or 8–14 post-immunization on T cell infiltration across the CP and EAE pathology. We determined the critical role of the CP-A(2A)R on T cell infiltration and EAE pathology by focal knock-down of CP-A(2A)R via intracerebroventricular injection of CRE-TAT recombinase into the A(2A)R(flox/flox) mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A(2A)Rs or the A(2A)R agonist CGS21680 treatment on the CP permeability and lymphocytes migration. RESULTS: We found the specific upregulation of A(2A)R in the CP associated with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8–12 or 8–14 post-immunization reduced T cell trafficking across the CP and attenuated EAE pathology. Importantly, focal CP-A(2A)R knock-down attenuated the pathogenic infiltration of Th17(+) cells across the CP via inhibiting the CCR6–CCL20 axis through NFκB/STAT3 pathway and protected against EAE pathology. Lastly, activation of A(2A)R in the cultured epithelium by A(2A)R overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration. CONCLUSION: These findings define the CP niche as one of the primary sites of A(2A)R action, whereby A(2A)R antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A(2A)R represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02415-z. |
format | Online Article Text |
id | pubmed-8855604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-88556042022-02-23 Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis Zheng, Wu Feng, Yijia Zeng, Zhenhai Ye, Mengqian Wang, Mengru Liu, Xin Tang, Ping Shang, Huiping Sun, Xiaoting Lin, Xiangxiang Wang, Muran Li, Zhengzheng Weng, Yiyun Guo, Wei Vakal, Sergii Chen, Jiang-fan J Neuroinflammation Research BACKGROUND: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A(2A) receptor (A(2A)R) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A(2A)R-mediated protection remains undetermined. METHODS: In the EAE model, we assessed A(2A)R expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A(2A)R antagonist KW6002 treatment at days 8–12 or 8–14 post-immunization on T cell infiltration across the CP and EAE pathology. We determined the critical role of the CP-A(2A)R on T cell infiltration and EAE pathology by focal knock-down of CP-A(2A)R via intracerebroventricular injection of CRE-TAT recombinase into the A(2A)R(flox/flox) mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A(2A)Rs or the A(2A)R agonist CGS21680 treatment on the CP permeability and lymphocytes migration. RESULTS: We found the specific upregulation of A(2A)R in the CP associated with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8–12 or 8–14 post-immunization reduced T cell trafficking across the CP and attenuated EAE pathology. Importantly, focal CP-A(2A)R knock-down attenuated the pathogenic infiltration of Th17(+) cells across the CP via inhibiting the CCR6–CCL20 axis through NFκB/STAT3 pathway and protected against EAE pathology. Lastly, activation of A(2A)R in the cultured epithelium by A(2A)R overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration. CONCLUSION: These findings define the CP niche as one of the primary sites of A(2A)R action, whereby A(2A)R antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A(2A)R represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02415-z. BioMed Central 2022-02-18 /pmc/articles/PMC8855604/ /pubmed/35180864 http://dx.doi.org/10.1186/s12974-022-02415-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zheng, Wu Feng, Yijia Zeng, Zhenhai Ye, Mengqian Wang, Mengru Liu, Xin Tang, Ping Shang, Huiping Sun, Xiaoting Lin, Xiangxiang Wang, Muran Li, Zhengzheng Weng, Yiyun Guo, Wei Vakal, Sergii Chen, Jiang-fan Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis |
title | Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis |
title_full | Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis |
title_fullStr | Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis |
title_full_unstemmed | Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis |
title_short | Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis |
title_sort | choroid plexus-selective inactivation of adenosine a(2a) receptors protects against t cell infiltration and experimental autoimmune encephalomyelitis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855604/ https://www.ncbi.nlm.nih.gov/pubmed/35180864 http://dx.doi.org/10.1186/s12974-022-02415-z |
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