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

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.

Activation of RARα Receptor Attenuates Neuroinflammation After SAH via Promoting M1-to-M2 Phenotypic Polarization of Microglia and Regulating Mafb/Msr1/PI3K-Akt/NF-κB Pathway

“…Depending on the intervening conditions, bipolar microglia can differentiate into two distinct phenotypes (42,43). At the same time, an increase in M2 phenotype microglia after SAH, which is associated with better neurological prognosis, has also been demonstrated in many studies (7,44,45). These results suggest that promoting the transition of microglia from M1 to M2 phenotype in the early stage after SAH may be beneficial to reduce neuroinflammatory damage after SAH and accelerate the recovery of neurological function.…”

Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway

“…Zhou et al suggested that activation of SIRT1 promoted mitochondrial biogenesis and reduced apoptosis after intracerebral hemorrhage [ 37 ]. In SAH, several studies have showed that activation of SIRT1 by pharmacological therapies could ameliorate neuroinflammation and oxidative insults, and improve motor functions [ 38 – 40 ]. In addition, SIRT1 has the potential to ameliorate cerebral vasospasm after SAH [ 14 ].…”

Alantolactone reduced neuron injury via activating PI3K/Akt signaling pathway after subarachnoid hemorrhage in rats

“…It has been shown that SAH induced microglia activation, and promoted the level of M1-type microglial markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome [45]. Furthermore, SAH caused the microglia polarization shift from the M2 phenotype and skewed toward the M1 phenotype [46], evidenced by the increased levels of IL-6, IL-1β, and TNF-α [47]. Similarly, our data showed that SAH promoted the expression of pro-inflammatory, suppressed IL-10 expression, and stimulated changes in polarization from the M2 to the M1 phenotype in microglia, which were reversed by ATL treatment.…”