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

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

Authors Pu Z , Bao X, Xia S, Shao P, Xu Y

Received 10 February 2022

Accepted for publication 7 April 2022

Published 24 April 2022 Volume 2022:15 Pages 2649—2663

DOI https://doi.org/10.2147/JIR.S361072

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Ning Quan

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Zhijun Pu,^{1– 5} Xinyu Bao,^{1– 5} Shengnan Xia,^{1– 5} Pengfei Shao,^{1– 5} Yun Xu<sup>1– 5

1</sup>Department of Neurology, Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China; ²Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu, 210093, People’s Republic of China; ³Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China; ⁴Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu, 210008, People’s Republic of China; ⁵Nanjing Neurology Clinic Medical Center, Nanjing, Jiangsu, 210008, People’s Republic of China

Correspondence: Yun Xu, Email xuyun20042001@aliyun.com

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

Introduction

Stroke is a devastating disease with a high rate of death and a major cause of acquired disability in adults.¹ Ischemic stroke is the majority of strokes, but few curative therapeutic strategies are available. Thus far, tissue-type plasminogen activator and thrombectomy are the only clinically approved treatments for acute ischemic stroke, and there is substantial agreement between vascular neurology fellows.² However, the treatment time window is particularly important for ischemic stroke, within 0 to 4.5 h, which also limits the scope of application of tissue-type plasminogen activator and thrombectomy.

Peripheral immune cells have been widely reported to be activated and recruited into the ischemic hemisphere and exert elaborate functions, which is one of the key features of the neuroimmunological reaction to cerebral ischemia.^3,4 Among peripheral immune cells, neutrophils are the first to infiltrate the ischemic brain and are widely reported to play an important role in determining the outcome of ischemic stroke.⁵ In the acute phase of poststroke inflammation, following the large release of inflammatory cytokines and chemokines, neutrophils are recruited into the ischemic hemisphere and exacerbate ischemic injury by damaging neural cells.⁶ Inhibition of neutrophil infiltration, therefore, might represent a new therapeutic intervention for neuroprotection in the acute stages of ischemic stroke.^3,7

Dauricine (C₃₈H₄₄N₂O₆) is an isoquinoline alkaloid and has rich pharmacological activity, including anti-Alzheimer’s disease,^8,9 resistance to intracerebral hemorrhage and transient focal cerebral ischemia,^10,11 which are known mechanisms involved in antioxidative, antiapoptosis, and anti-inflammatory activities.^12,13 Dauricine is able to quickly pass through the blood-brain barrier, which is the material basis of neuroprotection.¹⁴ Although these previous studies suggest the neuroprotection of dauricine in the transient middle cerebral artery and the potential medicinal value of dauricine, the neuron-immune actions and therapeutic prospects of dauricine in acute neuronal injury have not been investigated well.

In this study, we examined whether dauricine has potential ameliorative effects against brain I/R injury and investigated the underlying mechanisms in vivo, mainly focusing on the infiltration of peripheral immune cells into the brain by using an experimental model of focal cerebral ischemia–reperfusion.

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