Adenosine A(2A) Receptor in Bone Marrow-Derived Cells Mediated Macrophages M2 Polarization via PPARγ-P65 Pathway in Chronic Hypoperfusion Situation.
Adenosine A(2A) Receptor in Bone Marrow-Derived Cells Mediated Macrophages M2 Polarization via PPARγ-P65 Pathway in Chronic Hypoperfusion Situation.
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在慢性灌注不足的情况下，骨髓衍生细胞中的腺苷A（2a）受体通过PPARγ-P65途径介导了巨噬细胞M2极化。
DOI：
10.3389/fnagi.2021.792733
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发表时间：
2021
影响因子：
4.8
通讯作者：
Duan W
中科院分区：
文献类型：
--
作者：
Mou KJ;Shen KF;Li YL;Wu ZF;Duan W
背景：腺苷A2 A受体（A2 AR）在慢性脑低灌注所致缺血性白色损害中的作用尚不清楚。本研究旨在探讨A2 AR在慢性脑低灌注所致的白色损害中巨噬细胞极化过程中的作用及其信号转导途径。方法：采用小鼠模型和巨噬细胞系相结合的方法进行研究。通过双侧颈总动脉狭窄在A2 AR敲除小鼠、野生型小鼠和通过骨髓细胞移植产生的嵌合小鼠中诱导白色病变。通过免疫荧光检测胼胝体中的小胶质细胞/巨噬细胞极化。对于细胞系实验，用A2 AR激动剂CHS 21680或A2 AR拮抗剂SCH 58261处理RAW 264.7巨噬细胞30分钟，并在低葡萄糖和缺氧条件下培养。免疫荧光法检测巨噬细胞极化。采用Western blotting和实时荧光定量PCR（real-time polymerase chain reaction，RT-PCR）检测细胞过氧化物酶体增殖物激活受体γ（peroxisome proliferator activated receptor gamma，PPARγ）和转录因子P65的表达。采用酶联免疫吸附试验（ELISA）和RT-PCR检测炎症细胞因子。结果如下：在慢性缺血性白色病变中，骨髓源性细胞中A2 AR的整体敲除和A2 AR的失活均增强了M1标记物的表达。在低糖低氧条件下，CGS 21680可促进巨噬细胞M2极化，增加PPARγ、P65和IL-10的表达，抑制肿瘤坏死因子-α（TNF-α）和IL-1β（IL-1β）的表达。CGS 21680诱导的巨噬细胞P65和IL-10的上调在PPARγ敲低后被消除。CGS 21680对TNF-α和IL-1β的下调作用不受PPARγ基因敲低的影响。结论：在脑低灌注所致的白色物质损伤中，骨髓源性细胞A2 AR信号通过PPARγ-P65通路诱导巨噬细胞M2极化并增加抗炎因子IL-10的表达，这可能是其神经保护作用的原因。
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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影响因子：
4
作者：
Jin, Jing;Guo, Jia;Ge, Zhao-Ming
通讯作者：
Ge, Zhao-Ming
选择性腺苷A2A受体激动剂和拮抗剂通过外周和中心作用预防脊髓损伤。
影响因子：
9.3
作者：
Paterniti I;Melani A;Cipriani S;Corti F;Mello T;Mazzon E;Esposito E;Bramanti P;Cuzzocrea S;Pedata F
通讯作者：
Pedata F
影响因子：
9.3
作者：
Chu, Tianci;Zhang, Yi Ping;Cai, Jun
通讯作者：
Cai, Jun
影响因子：
3.8
作者：
Ahmad, Sheikh F.;Ansari, Mushtaq A.;Attia, Sabry M.
通讯作者：
Attia, Sabry M.
影响因子：
4.6
作者：
Lei Li-Yan;Wang Rui-Cheng;Tang Zhi-Shu
通讯作者：
Tang Zhi-Shu