PPP1R15A Promotes Apoptosis, Autophagy, and Inflammatory Response to Exacerbate Ischemic Stroke Through Activation of TLR4/NF-κB Pathway

Abstract

Ischemic stroke (IS) is a prevalent and serious neurological disorder, and is one of the major contributors to mortality and disability worldwide. The activation of autophagy and the inflammatory response following cerebral ischemia are crucial in the progression of IS. Protein phosphatase 1 regulatory subunit 15A (PPP1R15A), as a stress-responsive protein, has been proven to be closely associated with autophagy. Nevertheless, the molecular mechanism of PPP1R15A in IS remains to be fully understood. Our study screened PPP1R15A as a candidate gene by bioinformatics analysis of the differentially expressed genes (DEGs) in IS and autophagy-related genes (ARGs). Functionally, experiments uncovered that down-regulation of PPP1R15A alleviated oxygen–glucose deprivation/reoxygenation (OGD/R)-mediated inhibition of cell viability and promotion of LDH release, cell apoptosis, autophagy, and inflammation in A172 and SH-SY5Y cells. Simultaneously, silencing PPP1R15A ameliorated the IS progression in the middle cerebral artery occlusion and reperfusion (MCAO/R) rat model. Furthermore, PPP1R15A activated the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway in vivo and in vitro. Rescue experiments indicated that TLR4 inhibitors TAK-242 and NF-κB inhibitors BAY-11-7082 effectively alleviated the malignant progression of IS mediated by overexpression of PPP1R15A. Our data illustrated that PPP1R15A promoted OGD/R-induced cytotoxicity, apoptosis, autophagy, and inflammation by activating the TLR4/NF-κB pathway.