SENP1 modulates chronic intermittent hypoxia-induced neuroinflammation and neuronal injury by inhibiting microglial migration via the de-SUMOylation of TOM1

Abstract

Abstract Chronic intermittent hypoxia (CIH), a prominent characteristic of obstructive sleep apnea syndrome, accelerates OSAS-associated neurocognitive impairment by initiating neuroinflammation. Microglia play a vital role in neuronal development and detrimental phagocytosis through migration. SUMO-specific proteases 1 (SENP1) has been implicated in cells migration. However, the role of SENP1 in the progression of CIH-induced neuroinflammation of microglia remains unknown. We aimed to investigate the effect of SENP1 on microglial migration, neuroinflammation, neuronal injury and Aβ deposition after the CIH insult. The CIH model was established using an intermittent hypoxia device. SENP1 overexpression and knockdown were induced in vitro and in vivo, respectively. Results showed that CIH downregulated the expression of both SENP1 and TOM1, enhanced the SUMOylation of TOM1, and promoted microglial migration, neuroinflammation, neuronal apoptosis and neuronal Aβ42 deposition in vitro and in vivo. After SENP1 overexpression in vitro, the enhanced SUMOylation of TOM1 was inhibited; the expression of TOM1 and microglial migration were enhanced; neuroinflammation, neuronal apoptosis and neuronal accumulation of Aβ42 by CIH was significantly reduced. However, the administration of siRNA-TOM1 abolished the microglial migration, neuroinflammation, neuronal apoptosis and reduction of Aβ42 deposition. After SENP1 knockdown in vivo, the SUMOylation enhancement of TOM1 was accelerated, microglial migration was inhibited. Neuroinflammation, neuronal apoptosis, neuronal Aβ42 deposition, cognitive impairment was significantly aggrandized. Overall, the results demonstrated that SENP1 promoted microglial migration by regulating the de-SUMOylation of TOM1, thus contributing to neuroinflammation, neuronal apoptosis and the clearance of Aβ42 deposition induced by CIH injury.