Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro.
Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro.
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DOI：
10.1038/s41598-018-20733-2
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发表时间：
2018-02-02
影响因子：
4.6
通讯作者：
Langmann T
中科院分区：
文献类型：
--
作者：
Madeira MH;Rashid K;Ambrósio AF;Santiago AR;Langmann T
黄斑变性（AMD）是一种以视网膜色素上皮（RPE）的病理变化和光感受器的丧失为特征的疾病。越来越多的证据表明，反应性小胶质细胞触发RPE功能障碍和光感受器的损失，并且炎性体途径和补体激活有助于AMD发病机制。我们和其他人先前已经表明，腺苷A2 A受体（A2 AR）阻断剂可预防小胶质细胞介导的神经炎症过程，并介导对视网膜的保护。然而，阻断小胶质细胞中的A2 AR是否可以保护AMD的病理特征仍然是未知的。在本文中，我们表明，A2 AR拮抗剂，SCH 58261，防止上调的促炎介质的表达和补体系统中的变化触发的炎症挑战在人类小胶质细胞。此外，阻断小胶质细胞中的A2 AR降低了暴露于活化的小胶质细胞的条件培养基的ARPE-19细胞中的炎症反应以及补体和炎性体活化。最后，我们还表明，在人类小胶质细胞中阻断A2 AR增加了凋亡光感受器的清除。本研究通过调节小胶质细胞、RPE和光感受器之间的相互作用，开启了使用选择性A2 AR拮抗剂治疗AMD的可能性。
Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A2A receptor (A2AR) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A2AR in microglia protects against the pathological features of AMD. Herein, we show that an A2AR antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A2AR in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE-19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A2AR in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A2AR antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors.
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影响因子：
11.1
作者：
Karlstetter M;Kopatz J;Aslanidis A;Shahraz A;Caramoy A;Linnartz-Gerlach B;Lin Y;Lückoff A;Fauser S;Düker K;Claude J;Wang Y;Ackermann J;Schmidt T;Hornung V;Skerka C;Langmann T;Neumann H
通讯作者：
Neumann H
影响因子：
4.6
作者：
Gao J;Liu RT;Cao S;Cui JZ;Wang A;To E;Matsubara JA
通讯作者：
Matsubara JA
影响因子：
4.7
作者：
Harrigan TJ;Abdullaev IF;Jourd'heuil D;Mongin AA
通讯作者：
Mongin AA
DOI：
10.1038/gim.2015.70
发表时间：
2016-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Black JR;Clark SJ
通讯作者：
Clark SJ
影响因子：
4.4
作者：
Ablonczy, Zsolt;Dahrouj, Mohammad;Crosson, Craig E.
通讯作者：
Crosson, Craig E.