Choroid plexus-selective inactivation of adenosine A2A receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis

Wu Zheng, Yijia Feng, Zhenhai Zeng, Mengqian Ye, Mengru Wang, Xin Liu, Ping Tang, Huiping Shang, Xiaoting Sun, Xiangxiang Lin, Muran Wang, Zhengzheng Li, Yiyun Weng, Wei Guo, Sergii Vakal, Jiang-fan Chen

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Abstract

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 2AR) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A 2AR-mediated protection remains undetermined. Methods: In the EAE model, we assessed A 2AR expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A 2AR 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 2AR on T cell infiltration and EAE pathology by focal knock-down of CP-A 2AR via intracerebroventricular injection of CRE-TAT recombinase into the A 2AR flox/flox mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A 2ARs or the A 2AR agonist CGS21680 treatment on the CP permeability and lymphocytes migration. Results: We found the specific upregulation of A 2AR 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 2AR 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 2AR in the cultured epithelium by A 2AR 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 2AR action, whereby A 2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A 2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP.

Original languageEnglish
Article number52
JournalJournal of Neuroinflammation
Volume19
Issue number1
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Keywords

  • Choroid plexus
  • Leukocytes, Mononuclear/cytology
  • Adenosine A receptors

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