Blocking the A2B adenosine receptor alleviates myocardial damage by inhibiting spleen-derived MDSC mobilisation after acute myocardial infarction

Myeloid-derived suppressor cell (MDSC) mobilisation is an important immune event in acute myocardial infarction (AMI). The A2B adenosine receptor (A2BAR) plays key role in regulating MDSC function, but its specific involvement in MDSC mobilisation in AMI remains unclear. In AMI patients, the circulating MDSC ratio and A2BAR mRNA expression were measured. A mouse AMI model was established by left anterior descending coronary artery (LADCA) ligation. MDSCs were analysed by FACS and immunofluorescence staining (of heart tissue). A2BAR mRNA expression was assessed by qRT-PCR. Myocardial injury was detected by HE staining. Myocardial cell apoptosis was analysed by immunohistochemistry. Cardiac systolic function was evaluated by transthoracic echocardiography. In AMI patients, the circulating MDSC ratio was increased and positively correlated with A2BAR mRNA expression (r = 0.86, p 2BAR inhibition decreased the MDSC ratio in the circulation and infarcted heart and prevented the decrease in MDSC number in the spleens of mice with AMI. A2BAR blockade inhibited myocardial cell apoptosis, alleviated myocardial inflammatory injury, and improved myocardial systolic function in the AMI mouse model. Similar results were found in mice after splenectomy. Additionally, spleen-derived MDSC injection increased the MDSC ratio in the infarcted heart, increased myocardial cell apoptosis, aggravated myocardial injury, and decreased cardiac systolic function in mice with AMI. Blocking A2BAR alleviates myocardial damage and improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation after AMI. Key MessagesSpleen-derived MDSC mobilisation aggravates myocardial inflammatory injury within 24 h of AMI.A2BAR promotes spleen-derived MDSC mobilisation within 24 h of AMI.Blocking A2BAR improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation. Spleen-derived MDSC mobilisation aggravates myocardial inflammatory injury within 24 h of AMI. A2BAR promotes spleen-derived MDSC mobilisation within 24 h of AMI. Blocking A2BAR improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation.

髓系来源抑制性细胞（Myeloid-derived suppressor cell, MDSC）动员是急性心肌梗死（acute myocardial infarction, AMI）中重要的免疫事件。A2B腺苷受体（A2B adenosine receptor, A2BAR）在调控MDSC功能中发挥关键作用，但其在急性心肌梗死患者MDSC动员过程中的具体参与机制尚未阐明。
本研究检测了急性心肌梗死患者外周血MDSC比例及A2BAR mRNA表达水平。通过结扎左前降支冠状动脉（left anterior descending coronary artery, LADCA）构建小鼠急性心肌梗死模型。采用流式细胞术（Fluorescence Activated Cell Sorting, FACS）与免疫荧光染色（针对心脏组织）分析MDSCs；通过实时定量逆转录聚合酶链反应（qRT-PCR）检测A2BAR mRNA表达；通过苏木精-伊红（HE）染色评估心肌损伤程度；通过免疫组织化学分析心肌细胞凋亡水平；经胸超声心动图评价心脏收缩功能。
急性心肌梗死患者外周血MDSC比例升高，且与A2BAR mRNA表达呈正相关（r=0.86，P<0.05）；A2BAR抑制可降低急性心肌梗死小鼠循环系统及梗死心脏中的MDSC比例，逆转脾脏中MDSC数量的减少。A2BAR阻断可抑制急性心肌梗死小鼠模型中的心肌细胞凋亡，减轻心肌炎性损伤，并改善心脏收缩功能。该结果在脾切除术后的小鼠中同样得到验证。此外，向急性心肌梗死小鼠输注脾脏来源的MDSCs可升高梗死心脏中的MDSC比例，增加心肌细胞凋亡，加重心肌损伤，并降低心脏收缩功能。
综上，阻断A2BAR可通过抑制急性心肌梗死发生后脾脏来源的MDSC动员，减轻心肌损伤并改善心脏收缩功能。
关键研究结论：
1. 急性心肌梗死发生24小时内，脾脏来源的髓系来源抑制性细胞动员可加重心肌炎性损伤；
2. A2BAR可促进急性心肌梗死发生24小时内脾脏来源的髓系来源抑制性细胞动员；
3. 阻断A2BAR可通过抑制脾脏来源的髓系来源抑制性细胞动员，改善心脏收缩功能。
脾脏来源的髓系来源抑制性细胞动员可在急性心肌梗死发生24小时内加重心肌炎性损伤；A2BAR可促进急性心肌梗死发生24小时内脾脏来源的髓系来源抑制性细胞动员；阻断A2BAR可通过抑制脾脏来源的髓系来源抑制性细胞动员，改善心脏收缩功能。