IL-17A Enhances Microglial Response to OGD by Regulating p53 and PI3K/Akt Pathways with Involvement of ROS/HMGB1.

Bin Zhang,Feng Zhang,Zhi-Ming Mo,Ning Yang,Shao-Peng Lin

doi:10.3389/fnmol.2017.00271

Abstract

Cerebral ischemia-reperfusion injury (IRI) has a complex pathogenesis, and interleukin-17 (IL-17) is a newly identified class of the cytokine family that plays an important role in ischemic inflammation. An oxygen-glucose deprivation (OGD) model showed that IL-17A expression was significantly up-regulated in microglial cells. After IL-17A siRNA transfection, the inhibition of proliferation, and the increased apoptosis in microglial cells, induced by OGD/reperfusion, was improved, and the elevation of Caspase-3, Caspase-8, Caspase-9, and poly ADP ribose polymerase (PARP) activities was inhibited. Mass spectrometry demonstrated that IL-17A functioned through a series of factors associated with oxidative stress and apoptosis and regulated Caspase-3 activity and apoptosis in microglial cells via the p53 and PI3K/Akt signaling pathways. IL-17A, HMGB1, and ROS were regulated mutually to exhibit a synergistic effect in the OGD model of microglial cells, but the down-regulation of IL-17A or HMGB1 expression did not completely inhibit the production of ROS. These findings demonstrated that ROS might be located upstream of IL-17A and HMGB1 so that ROS can regulate HMGB1/IL-17A expression to affect the p53 and PI3K/Akt signaling pathways and therefore promote the occurrence of apoptosis in microglial cells. These findings provide a novel evidence for the role of IL-17A in ischemic cerebral diseases.

Highlights

Cerebral ischemia is a common disease that severely endangers human health, and it is characterized by a high incidence, high disability rate, high mortality, and high recurrence rate (Mellado et al, 2005; Chen et al, 2013)
A model of oxygen-glucose deprivation (OGD) was established to simulate cerebral ischemia-reperfusion in vitro, and a significant up-regulation of IL-17A expression was found during OGD/reperfusion, while the addition of siRNA caused a reduction in IL-17A expression by using the expression of beta-actin in cells as internal reference (Figure 1)
By targeting microglial cells, a model of OGD was established to simulate the development of cerebral ischemia-reperfusion injury (IRI) in vitro, and IL-17A expression was significantly up-regulated in the OGD group

Summary

Introduction

Cerebral ischemia is a common disease that severely endangers human health, and it is characterized by a high incidence, high disability rate, high mortality, and high recurrence rate (Mellado et al, 2005; Chen et al, 2013). By in situ hybridization and immunohistochemistry, IL-17 expression gradually increases in the cerebrum tissues of rats from 1 h to 6 days following cerebral ischemia, and the T cell infiltration correlates positively with the area of the cerebral injury, which demonstrates that IL17 and T cells are involved in cerebral injury (Li et al, 2005). The T cells, IL-23, and IL-17 that infiltrate into the ischemic cerebral tissues is critical to cerebral infarction formation and neurologic impairment, and IL-17 is reported to play an important role in the delayed phase of ischemia and reperfusion, namely, at the time of neuronal cell apoptosis and necrosis (Shichita et al, 2009). It is considered that IL-17 is of great significance in the development and progression of cerebral IRI

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