Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury by Modulating Microglial Polarization Through TXNIP/NLRP3 Signaling Pathway in Mice

Abstract

Microglial polarization is associated with cerebral ischemia/reperfusion (I/R) injury: a life-threatening disorder with high morbidity and mortality. Low-density lipoprotein receptor-related protein-1 (LRP1) has multiple properties, including anti-inflammation and anti-oxidation. Thioredoxin-interacting protein (TXNIP), an inhibitor of thioredoxin, plays a crucial role in oxidative stress and inflammation. However, whether LRP1 activation can alleviate I/R-induced cerebral damage and whether TXNIP is involved in the above effects is yet unknown. The present study aimed to investigate the effects of LRP1 activation on cerebral I/R injury and elucidate its underlying mechanism. Cerebral I/R injury was induced in mice by bilateral common carotid arteries occlusion. LPR1 ligand, apoE-mimic peptide COG1410 was administered intraperitoneally. Overexpression of TXNIP was achieved via the hippocampal injection of AAV-TXNIP before COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, western blot, enzyme-linked immunosorbent assay, HE and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Our results showed that the expressions of LRP1, TXNIP, and NLRP3 inflammasome were increased after cerebral I/R. COG1410 significantly ameliorated cerebral I/R-induced neurobehavioral deficits, brain edema, histopathological damage, and poor survival rate. Interestingly, COG1410 increased the anti-inflammatory M2 microglial phenotypes, decreased oxidative stress, attenuated apoptosis, and inhibited the expression of the TXNIP/NLRP3 signaling pathway. However, the benefits of COG1410 were reversed by TXNIP overexpression. Thus, our study suggested that LRP1 activation with COG1410 attenuated cerebral I/R injury at least partially by modulating M2 microglial polarization through TXNIP/NLRP3 signaling pathway in mice. Thus, COG1410 might serve as a promising treatment in the management of cerebral I/R patients.

Note:
Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81873930), partly by grants from the Department of Science and Technology of Sichuan Province (No.20YYJC2019), the Talent development project of The Affiliated Hospital of Southwest Medical University (No.20063), and the Youth Program of Southwest Medical University (No.2021ZKQN057).

Declaration of Interests: The authors declare that they have no conflicts of interest.

Ethics Approval Statement: The current study was approved by the Animal Care Committee of Southwest Medical University (China).

Keywords: cerebral ischemia-reperfusion, LRP1, apoE, microglia, neuroinflammation