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Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury.

ABSTRACT: The mechanism of cognitive dysfunction caused by ischemic white matter lesions is unclear. To explore the effect and mechanism of different cell-derived adenosine A2A receptor (A2AR) in cognitive impairment caused by chronic hypoperfusion white matter lesions (CHWMLs), we destroyed the bone marrow hematopoietic capacity of the recipient mice using radiation irradiation followed by establishing the selectively inactivated or reconstituted A2AR models with the transplanting bone marrow from global A2AR gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Then Morris Water Maze (MWM), ELISA, immunohistochemistry, and Bielschowsky silver staining were used to assess the effect and mechanism of the cognitive function in chronic cerebral blood flow hypoperfusion (CCH) model. Selectively reconstructing bone marrow-derived cells (BMDCs) A2AR (WT???KO group) and activated total adenosine A2AR with CGS21680 (CCH?+?CGS group) improved the cognitive related index. Activation of BMDC A2AR suppressed expression of inflammatory cytokines in peripheral blood and reduced the number of activated microglia cells co-localized with cystatin F in local brain, consequently inhibited white matter lesions. On the contrary, selective inactivation of adenosine A2AR (KO???WT group) and activation of non-BMDC A2AR with CGS21680 (KO???WT?+?CGS group) served the opposite effects. These results suggested that BMDC A2AR could inhibit white matter lesions and attenuate cognitive impairment after CHWMLs, whereas non-BMDC A2ARs aggravate cognitive impairment. The systemic inflammatory response and local activated microglia with cystatin F high expression were involved in the process of cognitive function recovery with BMDC A2AR. The overall trend is that BMDC A2ARs play a leading role.

SUBMITTER: Ran H

PROVIDER: S-EPMC7496018 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury.

Ran Hong H Yuan Jichao J Huang Jialu J Wang Jie J Chen Kangning K Zhou Zhenhua Z

Translational stroke research 20200511 5

The mechanism of cognitive dysfunction caused by ischemic white matter lesions is unclear. To explore the effect and mechanism of different cell-derived adenosine A2A receptor (A2AR) in cognitive impairment caused by chronic hypoperfusion white matter lesions (CHWMLs), we destroyed the bone marrow hematopoietic capacity of the recipient mice using radiation irradiation followed by establishing the selectively inactivated or reconstituted A2AR models with the tran ...[more]

PMID: 32394183

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Project description:White matter hyperintensities (WMHs) of presumed vascular origin are one of the most important neuroimaging markers of cerebral small vessel disease (CSVD), which are closely associated with cognitive impairment. The aim of this study was to elucidate the pathogenesis of WMHs from the perspective of inflammation and hypoperfusion mechanisms. A total of 65 patients with WMHs and 65 healthy controls were enrolled in this study. Inflammatory markers measurements [hypersensitive C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2)], cognitive evaluation, and pseudocontinuous arterial spin labeling (PCASL) MRI scanning were performed in all the subjects. The multivariate logistic regression analysis showed that Lp-PLA2 was an independent risk factor for WMHs. Cerebral blood flow (CBF) in the whole brain, gray matter (GM), white matter (WM), left orbital medial frontal gyrus [MFG.L (orbital part)], left middle temporal gyrus (MTG.L), and right thalamus (Tha.R) in the patients was lower than those in the controls and CBF in the left triangular inferior frontal gyrus [IFG.L (triangular part)] was higher in the patients than in the controls. There was a significant correlation between Lp-PLA2 levels and CBF in the whole brain (R = -0.417, p < 0.001) and GM (R = -0.278, p = 0.025), but not in the WM in the patients. Moreover, CBF in the MFG.L (orbital part) and the Tha.R was, respectively, negatively associated with the trail making test (TMT) and the Stroop color word test (SCWT), suggesting the higher CBF, the better executive function. The CBF in the IFG.L (triangular part) was negatively correlated with attention scores in the Cambridge Cognitive Examination-Chinese Version (CAMCOG-C) subitems (R = -0.288, p = 0.020). Our results revealed the vascular inflammation roles in WMHs, which may through the regulation of CBF in the whole brain and GM. Additionally, CBF changes in different brain regions may imply a potential role in the modulation of cognitive function in different domains.

Project description:Background: The role of adenosine A2A receptor (A2AR) in the ischemic white matter damage induced by chronic cerebral hypoperfusion remains obscure. Here we investigated the role of A2AR in the process of macrophage polarizations in the white matter damage induced by chronic cerebral hypoperfusion and explored the involved signaling pathways. Methods: We combined mouse model and macrophage cell line for our study. White matter lesions were induced in A2AR knockout mice, wild-type mice, and chimeric mice generated by bone marrow cells transplantation through bilateral common carotid artery stenosis. Microglial/macrophage polarization in the corpus callosum was detected by immunofluorescence. For the cell line experiments, RAW264.7 macrophages were treated with the A2AR agonist CHS21680 or A2AR antagonist SCH58261 for 30 min and cultured under low-glucose and hypoxic conditions. Macrophage polarization was examined by immunofluorescence. The expression of peroxisome proliferator activated receptor gamma (PPARγ) and transcription factor P65 was examined by western blotting and real-time polymerase chain reaction (RT-PCR). Inflammatory cytokine factors were assessed by enzyme-linked immunosorbent assay (ELISA) and RT-PCR. Results: Both global A2AR knockout and inactivation of A2AR in bone marrow-derived cells enhanced M1 marker expression in chronic ischemic white matter lesions. Under low-glucose and hypoxic conditions, CGS21680 treatment promoted macrophage M2 polarization, increased the expression of PPARγ, P65, and interleukin-10 (IL-10) and suppressed the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The CGS21680-induced upregulation of P65 and IL-10 was abolished in macrophages upon PPARγ knockdown. The downregulation of TNF-α and IL-1β by CGS21680 was less affected by PPARγ knockdown. Conclusions: In the cerebral hypoperfusion induced white matter damage, A2AR signaling in bone marrow-derived cells induces macrophage M2 polarization and increases the expression of the anti-inflammatory factor IL-10 via the PPARγ-P65 pathway, both of which might explain its neuroprotective effect.

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Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury.

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Adenosine A<sub>2A</sub> Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury.

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