miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling

• Published in: Journal of neuroinflammation 2021-06, Vol.18 (1), p.133-133, Article 133
• Main Authors: Feng, Yan, Li, Yan, Zhang, Ying, Zhang, Bo-Hao, Zhao, Hui, Zhao, Xin, Shi, Fu-Dong, Jin, Wei-Na, Zhang, Xiao-An
• Format: Article
• Language: English
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Carotid arteries; Cell activation; Cell cycle; Cellular signal transduction; Cerebral blood flow; Chemokines; Complications and side effects; Cytokines; Cytotoxicity; Development and progression; Disease Models, Animal; Experiments; Gene expression; Gene Expression Profiling; Genetic aspects; Health aspects; Immune suppression; Immune system; Infarction, Middle Cerebral Artery - diagnostic imaging; Infarction, Middle Cerebral Artery - metabolism; Ischemia; Ischemic stroke; Ischemic Stroke - diagnostic imaging; Ischemic Stroke - metabolism; Killer cells; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - metabolism; miRNA; Natural killer cells; Post-transcription; Poststroke infection; Signal Transduction; Software; Sp1 protein; Sp1 Transcription Factor - metabolism; Spleen; Stroke; Stroke (Disease); Surgery; Transcription factors; Transfection; Veins & arteries
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-021-02181-4

Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke. Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia. We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice. These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.