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Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

White matter lesions are an important pathological manifestation of cerebral small vessel disease, with inflammation playing a pivotal role in their development. The adenosine A2a receptor (ADORA2A) is known to inhibit the inflammation mediated by microglia, but its effect on astrocytes is unknown....

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Autores principales: Yuan, Jichao, Chen, Lin, Wang, Jie, Xia, Simin, Huang, Jialu, Zhou, Linke, Feng, Chengjian, Hu, Xiaofei, Zhou, Zhenhua, Ran, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882648/
https://www.ncbi.nlm.nih.gov/pubmed/35237278
http://dx.doi.org/10.3389/fimmu.2022.841290
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author Yuan, Jichao
Chen, Lin
Wang, Jie
Xia, Simin
Huang, Jialu
Zhou, Linke
Feng, Chengjian
Hu, Xiaofei
Zhou, Zhenhua
Ran, Hong
author_facet Yuan, Jichao
Chen, Lin
Wang, Jie
Xia, Simin
Huang, Jialu
Zhou, Linke
Feng, Chengjian
Hu, Xiaofei
Zhou, Zhenhua
Ran, Hong
author_sort Yuan, Jichao
collection PubMed
description White matter lesions are an important pathological manifestation of cerebral small vessel disease, with inflammation playing a pivotal role in their development. The adenosine A2a receptor (ADORA2A) is known to inhibit the inflammation mediated by microglia, but its effect on astrocytes is unknown. Additionally, although the level of YKL-40 (expressed mainly in astrocytes) has been shown to be elevated in the model of white matter lesions induced by chronic cerebral hypoperfusion, the specific regulatory mechanism involved is not clear. In this study, we established in vivo and in vitro chronic cerebral hypoperfusion models to explore whether the ADORA2A regulated astrocyte-mediated inflammation through STAT3/YKL-40 axis and using immunohistochemical, western blotting, ELISA, PCR, and other techniques to verify the effect of astrocytes ADORA2A on the white matter injury. The in vivo experiments showed that activation of the ADORA2A decreased the expression of both STAT3 and YKL-40 in the astrocytes and alleviated the white matter injury, whereas its inhibition had the opposite effects. Similarly, ADORA2A inhibition significantly increased the expression of STAT3 and YKL-40 in astrocytes in vitro, with more proinflammatory cytokines being released by astrocytes. STAT3 inhibition enhanced the inhibitory effect of ADORA2A on YKL-40 synthesis, whereas its activation reversed the phenomenon. These results suggest that the activation of ADORA2A in astrocytes can inhibit the inflammation mediated by the STAT3/YKL-40 axis and thereby reduce white matter injury in cerebral small vessel disease.
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spelling pubmed-88826482022-03-01 Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions Yuan, Jichao Chen, Lin Wang, Jie Xia, Simin Huang, Jialu Zhou, Linke Feng, Chengjian Hu, Xiaofei Zhou, Zhenhua Ran, Hong Front Immunol Immunology White matter lesions are an important pathological manifestation of cerebral small vessel disease, with inflammation playing a pivotal role in their development. The adenosine A2a receptor (ADORA2A) is known to inhibit the inflammation mediated by microglia, but its effect on astrocytes is unknown. Additionally, although the level of YKL-40 (expressed mainly in astrocytes) has been shown to be elevated in the model of white matter lesions induced by chronic cerebral hypoperfusion, the specific regulatory mechanism involved is not clear. In this study, we established in vivo and in vitro chronic cerebral hypoperfusion models to explore whether the ADORA2A regulated astrocyte-mediated inflammation through STAT3/YKL-40 axis and using immunohistochemical, western blotting, ELISA, PCR, and other techniques to verify the effect of astrocytes ADORA2A on the white matter injury. The in vivo experiments showed that activation of the ADORA2A decreased the expression of both STAT3 and YKL-40 in the astrocytes and alleviated the white matter injury, whereas its inhibition had the opposite effects. Similarly, ADORA2A inhibition significantly increased the expression of STAT3 and YKL-40 in astrocytes in vitro, with more proinflammatory cytokines being released by astrocytes. STAT3 inhibition enhanced the inhibitory effect of ADORA2A on YKL-40 synthesis, whereas its activation reversed the phenomenon. These results suggest that the activation of ADORA2A in astrocytes can inhibit the inflammation mediated by the STAT3/YKL-40 axis and thereby reduce white matter injury in cerebral small vessel disease. Frontiers Media S.A. 2022-02-14 /pmc/articles/PMC8882648/ /pubmed/35237278 http://dx.doi.org/10.3389/fimmu.2022.841290 Text en Copyright © 2022 Yuan, Chen, Wang, Xia, Huang, Zhou, Feng, Hu, Zhou and Ran https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yuan, Jichao
Chen, Lin
Wang, Jie
Xia, Simin
Huang, Jialu
Zhou, Linke
Feng, Chengjian
Hu, Xiaofei
Zhou, Zhenhua
Ran, Hong
Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions
title Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions
title_full Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions
title_fullStr Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions
title_full_unstemmed Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions
title_short Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions
title_sort adenosine a2a receptor suppressed astrocyte-mediated inflammation through the inhibition of stat3/ykl-40 axis in mice with chronic cerebral hypoperfusion-induced white matter lesions
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882648/
https://www.ncbi.nlm.nih.gov/pubmed/35237278
http://dx.doi.org/10.3389/fimmu.2022.841290
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