Critical Contribution of Adenosine A2A Receptors in Bone Marrow–Derived Cells to White Matter Lesions Induced by Chronic Cerebral Hypoperfusion
Critical Contribution of Adenosine A2A Receptors in Bone Marrow–Derived Cells to White Matter Lesions Induced by Chronic Cerebral Hypoperfusion
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DOI：
10.1097/nen.0000000000000174
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发表时间：
2015-04
影响因子：
3.2
通讯作者：
H-H Ran-H;W. Duan;Zi-li Gong;Senlin Xu;He Zhu;X. Hou;Li Jiang;Qifen He;Jian Zheng
中科院分区：
文献类型：
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作者：
H-H Ran-H;W. Duan;Zi-li Gong;Senlin Xu;He Zhu;X. Hou;Li Jiang;Qifen He;Jian Zheng
摘要不同细胞类型的腺苷A2 A受体（A2 ARs）对许多神经系统疾病可能产生不同甚至相反的作用;骨髓源性细胞（BMDCs）中的A2 ARs已被证明在各种脑损伤中起重要作用。我们以前表明，全球A2 AR失活加重慢性脑低灌注诱导的白色病变（WML），然而，负责A2 AR介导的信号的特定细胞群仍然未知。在本研究中，我们开发了嵌合小鼠，其中A2 AR选择性失活或重建BMDCs移植骨髓从全球A2 AR基因敲除或野生型小鼠到野生型或基因敲除小鼠，分别。随后通过双侧颈总动脉狭窄使嵌合小鼠经受慢性脑低灌注，并评估BMDC A2 AR对WML的影响。BMDCs中A2 AR的选择性失活加重了慢性脑低灌注诱导的WML，促进了小胶质细胞活化，并增加了促炎细胞因子的表达，而使用激动剂CGS 21680在BMDCs中A2 AR的选择性重建或活化产生了相反的效果。这些结果表明，在BMDCs中的A2 AR是慢性脑灌注不足诱导的WML的重要调节剂;这种调节可能与炎症细胞因子的产生的调节有关。
Abstract Adenosine A2A receptors (A2ARs) in distinct cellular types may exert different and even opposite effects on many neurologic disorders; A2ARs in bone marrow–derived cells (BMDCs) have been shown to play important roles in various brain injuries. We previously showed that global A2AR inactivation aggravates chronic cerebral hypoperfusion–induced white matter lesions (WMLs); however, the specific cell populations responsible for A2AR-mediated signaling remain unknown. In the present study, we developed chimeric mice in which A2ARs were either selectively inactivated or reconstituted in BMDCs by transplanting bone marrow from global A2AR gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Chimeric mice were subsequently subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis, and the effects of BMDC A2ARs on WMLs were evaluated. The selective inactivation of A2AR in BMDCs aggravated chronic cerebral hypoperfusion–induced WMLs, promoted microglial activation, and increased proinflammatory cytokine expression, whereas the selective reconstitution or activation of A2AR in BMDCs using the agonist CGS21680 produced the opposite effects. These results demonstrate that A2ARs in BMDCs are important modulators of WMLs induced by chronic cerebral hypoperfusion; this modulation might be associated with the regulation of inflammatory cytokine production.