Serpine1 Regulates Peripheral Neutrophil Recruitment and Acts as Potential Target in Ischemic Stroke

Abstract

Introduction

Peripheral neutrophil infiltration can exacerbate ischemia–reperfusion injury. We focused on the relationship between various peripheral immune cells and cerebral ischemia–reperfusion (I/R) injury.

Methods

In this study, we investigated the effects of dauricine on neuronal injury induced by ischemia–reperfusion and peripheral immune cells after ischemic stroke in mouse model, and we explored the undefined mechanisms of regulating peripheral immune cells through RNA sequencing and various biochemical verification in vitro and in vivo.

Results

We found that dauricine improved the neurological deficits of I/R injury, reduced the infarct volume, and improved the neurological scores. Furthermore, dauricine reduced the infiltration of neutrophils into the brain after MCAO-R and increased peripheral neutrophils but unchanged the permeability of the endotheliocyte Transwell system in an in vitro blood-brain barrier (BBB) model. RNA sequencing showed that chemotaxis factors, such as CXCL3, CXCL11, CCL20, CCL22, IL12a, IL23a, and serpine1, might play a crucial role. Overexpression of serpine1 reversed LPS-induced migration of neutrophils. Dauricine can directly bind with serpine1 in ligand–receptor docking performed with the Autodock and analyzed with PyMOL.

Conclusion

We identified chemotaxis factor serpine1 played a crucial role in peripheral neutrophil infiltration, which may contribute to reduce the neuronal injury induced by ischemia–reperfusion. These findings reveal that serpine1 may act as a potential treatment target in the acute stage of ischemic stroke.

Keywords:

• ischemia–reperfusion injury
• dauricine
• neutrophil recruitment
• serpine1

Acknowledgments

This research was supported by the National Natural Science Foundation of China (81920108017, 82130036, 81630028) and the Key Research and Development Program of Jiangsu Province of China (BE2020620). Jiangsu Province Key Medical Discipline (ZDXKA2016020).

Disclosure

All authors claim that there are no conflicts of interest and that none of the authors’ institutions has contracts relating to this research through which it may stand to gain financial support now or in the future.