Critical Contribution of Adenosine A_2AReceptors in Bone Marrow–Derived Cells to White Matter Lesions Induced by Chronic Cerebral Hypoperfusion

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.

Purinergic Signalling: Therapeutic Developments

“…A 2A R activation was suggested for the treatment of brain injury and subsequent neuroinflammation ( Dai and Zhou, 2011 ). A 2A R on cells derived from bone marrow modulate white matter lesions following chronic cerebral hypoperfusion ( Ran et al, 2015 ). Diadenosine tetraphosphate (Ap 4 A) may be a good candidate for traumatic spinal cord injury treatment ( Reigada et al, 2017 ).…”

Purinergic Signalling and Neurological Diseases: An Update

“…A2A receptor activation has been recommended for the treatment of brain injury and subsequent neuroinflammation [54]. A2A receptors on bone marrow-derived cells are modulators of white matter lesions induced by chronic cerebral hypoperfusion [55].…”

An adenosine�A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-κB and CREB phosphorylation

“…In addition, an A1R antagonist and A2aR agonist were applied to rebalance A1R-A2aR, which suppressed microglial activation and exhibited anti-inflammatory activity. Taking into account the results of our previous study, which identified that A2aR in bone marrow-derived dendritic cells is an important modulator of chronic cerebral hypoperfusion-induced WMLs (14), an A1R-A2aR imbalance may have important consequences for neuroinflammation and serve a role in the pathology of numerous cNS diseases.…”

“…Little is known about whether an imbalance of A1R to A2aR contributes to the immune cascade in microglia. Our group previously demonstrated that ablation of the A2aR gene promotes microglial activation and deteriorates chronic cerebral hypoperfusion-induced WMLs (14). Given that chronic cerebral ischemia can induce a downregulation of adenosine A1R during white matter damage, the functional antagonistic interactions between A1R and A2aR that modulate the release of inflammatory cytokines from the microglia should be further investigated.…”