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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Yan Feng, Yan Li, Ying Zhang, Bo-Hao Zhang, Hui Zhao, Xin Zhao, Fu-Dong Shi, Wei-Na Jin, Xiao-An Zhang
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 18 Issue 1 Pg. 133 (Jun 12 2021) ISSN: 1742-2094 [Electronic] England
• PMID: 34118948 (Publication Type: Journal Article)

Chemical References

• MIRN1224 microRNA, mouse
• MicroRNAs
• Sp1 Transcription Factor

Topics

• Animals
• Brain (diagnostic imaging, metabolism)
• Disease Models, Animal
• Gene Expression Profiling
• Infarction, Middle Cerebral Artery (diagnostic imaging, metabolism)
• Ischemic Stroke (diagnostic imaging, metabolism)
• Killer Cells, Natural (immunology, metabolism, pathology)
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Signal Transduction
• Sp1 Transcription Factor (metabolism)