SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage.

Da-Yong Xia,Xiang-Sheng Zhang,Ling-Yun Wu,Nian-Sheng Lai,Min Qi,Jin-Long Yuan,Xiao-Chun Jiang

doi:10.3389/fimmu.2021.770744

Abstract

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

Highlights

Subarachnoid hemorrhage (SAH) is a fatal cerebral vascular disease with high morbidity and mortality worldwide
We evaluated the effects of sirtuin 1 (SIRT1) inhibition by EX527 on microglia polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation
Our data indicated that EX527 further induced M1 microglia (IBA1+/CD16/32+) polarization (P = 0.0084 for CD16/32 IOD, P = 0.0019 for CD16/32+IBA1+) and NLRP3 inflammasome activation (P = 0.0113 for NLRP3 IOD, P = 0.023 for NLRP3+IBA1+), with no statistical difference on M2 microglia (IBA1+/CD206+) transformation (P > 0.05) (Figures 1E–M)

Summary

Introduction

Subarachnoid hemorrhage (SAH) is a fatal cerebral vascular disease with high morbidity and mortality worldwide. Despite tremendous advances in diagnosis and neurosurgical care, it remains a difficult challenge to develop effective therapeutic interventions to improve SAH outcomes. Accumulating evidence suggests that the robust post-SAH inflammatory response plays a crucial role in causing early brain injury (EBI) after SAH [1,2,3]. With the occurrence of hemorrhage and ischemia, rapid influx of inflammatory cells, microglia activation, and an increase of proinflammatory cytokines production lead to neuronal cell death. Inflammatory cells could induce the generation of reactive oxygen species (ROS) to further aggravate EBI. Diminishing cerebral inflammation is a promising method to reduce EBI and improve brain recovery after SAH

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Results

Conclusion