Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis.
Choroid plexus-selective inactivation of adenosine A(2A) receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis.
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脉络丛选择性失活腺苷 A2A 受体可防止 T 细胞浸润和实验性自身免疫性脑脊髓炎
DOI：
10.1186/s12974-022-02415-z
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发表时间：
2022-02-18
影响因子：
9.3
通讯作者：
Chen JF
中科院分区：
文献类型：
--
作者：
Zheng W;Feng Y;Zeng Z;Ye M;Wang M;Liu X;Tang P;Shang H;Sun X;Lin X;Wang M;Li Z;Weng Y;Guo W;Vakal S;Chen JF
多发性硬化症（MS）是一种常见的自身免疫性疾病，其特征是免疫细胞向脑内浸润并脱髓鞘，而那他珠单抗（natalizumab）的免疫抑制副作用使我们将注意力集中在实验性自身免疫性脑脊髓炎（EAE）中第一波免疫细胞浸润的关键部位脉络丛（CP），以控制免疫细胞的运输。腺苷A2 A受体（AdenosineA 2Areceptor，A2 AR）是控制EAE发病机制的潜在药物靶点。然而，A2 AR介导的保护作用的细胞基础仍未确定。在EAE模型中，我们通过免疫组织化学和qPCR分析评估了CP中的A2 AR表达和白细胞运输决定簇。我们确定了在免疫后第8-12或8-14天A2 AR拮抗剂KW 6002处理对跨越CP和EAE病理的T细胞浸润的影响。我们通过将CRE-TAT重组酶脑室内注射到A2 ARflox/flox小鼠中，通过局灶性敲低CP-A2 AR来确定CP-A2 AR对T细胞浸润和EAE病理的关键作用。在培养的CP上皮中，我们还评估了A2 AR过表达或A2 AR激动剂CGS 21680处理对CP渗透性和淋巴细胞迁移的影响。我们发现在EAE小鼠中，与增强的CP网关活性相关的CP中A2 AR的特异性上调在免疫后第12天达到峰值。此外，在免疫后第8-12天或第8-14天的KW 6002处理减少了穿过CP的T细胞运输并减弱了EAE病理学。重点是，局灶性CP-A2 AR敲低可通过NFκB/STAT 3途径抑制CCR 6-CCL 20轴，从而减轻Th 17+细胞在CP上的致病性浸润，保护EAE病理; A2 AR过表达或CGS 21680处理后，激活培养上皮中的A2 AR，增加CP上皮的通透性，促进淋巴细胞迁移。这些发现将CP小生境定义为A2 AR作用的主要位点之一，由此A2 AR拮抗剂赋予针对EAE病理学的保护作用。在线版本包含补充材料，可通过10.1186/s12974-022-02415-z获得。
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 A2A receptor (A2AR) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A2AR-mediated protection remains undetermined. In the EAE model, we assessed A2AR expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A2AR 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-A2AR on T cell infiltration and EAE pathology by focal knock-down of CP-A2AR via intracerebroventricular injection of CRE-TAT recombinase into the A2ARflox/flox mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A2ARs or the A2AR agonist CGS21680 treatment on the CP permeability and lymphocytes migration. We found the specific upregulation of A2AR 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-A2AR 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 A2AR in the cultured epithelium by A2AR overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration. These findings define the CP niche as one of the primary sites of A2AR action, whereby A2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP. The online version contains supplementary material available at 10.1186/s12974-022-02415-z.
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DOI：
10.1056/nejmra1401483
发表时间：
2018-01-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Reich DS;Lucchinetti CF;Calabresi PA
通讯作者：
Calabresi PA
影响因子：
30.5
作者：
Reboldi, Andrea;Coisne, Caroline;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
2.9
作者：
Chen, Guo Qian;Chen, Yan Yan;Zheng, Rong Yuan
通讯作者：
Zheng, Rong Yuan
影响因子：
7.6
作者：
Bastia, E;Xu, YH;Schwarzschild, MA
通讯作者：
Schwarzschild, MA
DOI：
10.1016/j.amjmed.2020.05.049
发表时间：
2020-12
期刊：
The American journal of medicine
影响因子：
--
作者：
Hauser SL;Cree BAC
通讯作者：
Cree BAC