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.

Inducible miR-1224 silences cerebrovascular Serpine1 and restores blood flow to the stroke-affected site of the brain

“…A chemotactic effect of SERPINE1 responsible for exacerbation of stroke-related neuroinflammation by enhanced recruitment of peripheral neutrophil has been reported. 38 The study of established biomarkers of death from ischemic stroke versus stroke survival revealed SERPINE1 as part of a highly connective protein-protein interaction network associated with death caused by ischemic stroke. 39 In patients with pseudoxanthoma elasticum, a rare autosomal recessive disorder caused by pathogenic variants in the ABCC6 gene, a 4G/4G SERPINE1 genotype contributes to an added risk for developing ischemic stroke.…”

The atypical antidepressant tianeptine confers neuroprotection against oxygen–glucose deprivation

“…Transcription factor p53 was previously shown to accumulate during brain ischemia and to trigger apoptosis [ 30 , 79 ]. Further, a recent study suggested that Serpine1 acts as a main chemotaxis factor for inflammatory neutrophil migration into the ischemic penumbra, and its overexpression in ischemic stroke appears to worsen neuronal damage [ 56 ]. In our study, increased mRNA levels of p53 as well as Serpine1 were reduced in TIA-treated neurons.…”

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Patients with Chronic Internal Carotid Artery Occlusion Complicated by Cerebral Infarction

“…After cerebral infarction, neutrophils migrate toward the ischemic area through the disrupted blood-brain barrier under the mediation of cytokines and chemokines. 18 Meanwhile, neutrophils release oxygen radicals and matrix metalloproteinases to further disrupt the blood-brain barrier and recruit more immune cells, worsening tissue edema and inducing cell death. 19 A study revealed that inhibiting neutrophil aggregation in the ischemic penumbra could alleviate neurological deficits in mouse models.…”