Abstract
BackgroundNeuroinflammation and oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study is the first to show that activation of autophagy protein nuclear receptor binding factor 2 (NRBF2) could reduce endoplasmic reticulum stress (ERS)-associated inflammation and oxidative stress after SAH.MethodsMale C57BL/6J mice were subjected to endovascular perforation to establish a model of SAH. NRBF2 overexpression adeno-associated virus (AAV), NRBF2 small interfering RNAs (siRNA), lysosomal inhibitor-chloroquine (CQ), and late endosome GTPase Rab7 receptor antagonist-CID1067700 (CID) were used to investigate the role of NRBF2 in EBI after SAH. Neurological tests, brain water content, western blotting and immunofluorescence staining were evaluated.ResultsOur study found that the level of NRBF2 was increased after SAH and peaked at 24 h after SAH. In addition, we found that the overexpression of NRBF2 significantly improved neurobehavioral scores and reduced ERS, oxidative stress, and neuroinflammation in SAH, whereas the inhibition of NRBF2 exacerbated these phenotypes. In terms of mechanism, NRBF2 overexpression significantly promoted autophagosome maturation, with the downregulation of CHOP, Romo-1, TXNIP, NLRP3, TNF-α, and IL-1β expression through interaction with Rab7. The protective effect of NRBF2 on ERS-associated neuroinflammation and oxidative stress after SAH was eliminated by treatment with CQ. Meanwhile, it was also reversed by intraperitoneal injection of CID. Moreover, the MIT domain of NRBF2 was identified as a critical binding site that interacts with Rab7 and thereby promotes autophagosome maturation.ConclusionOur data provide evidence that the autophagy protein NRBF2 has a protective effect on endoplasmic reticulum stress-associated neuroinflammation and oxidative stress by promoting autophagosome maturation through interactions with Rab7 after SAH.
Highlights
Subarachnoid hemorrhage (SAH), a subtype of stroke, is caused mainly by aneurysm rupture, resulting in poor neurological deficits, and high morbidity and mortality [1, 2]
(i) we identified the increased level of nuclear receptor binding factor 2 (NRBF2) after subarachnoid hemorrhage (SAH) and the protective effect of NRBF2 on the modulation of endoplasmic reticulum stress (ERS)-associated neuroinflammation and oxidative stress. (ii) We further found that the protective effect of NRBF2 occurred through enhancing autophagosome maturation by interacting with Rab7. (iii) we demonstrated that the MIT domain of NRBF2 was necessary for the interaction between NRBF2 and Rab7
Effect of NRBF2 on short-term and long-term neurological function after SAH To investigate the potential role of NRBF2 in the pathological process after SAH, downregulation and upregulation of NRBF2 were performed with NRBF2 small interfering RNAs (siRNA) and NRBF2 overexpression mediated by adeno-associated virus (AAV)
Summary
Subarachnoid hemorrhage (SAH), a subtype of stroke, is caused mainly by aneurysm rupture, resulting in poor neurological deficits, and high morbidity and mortality [1, 2]. Studies of NRBF2 in Alzheimer’s disease revealed that NRBF2 plays an important role in regulating the degradation of APP C-terminal fragments by modulating autophagy and could be a potential therapeutic target for Alzheimer’s disease [11, 13]. Cai et al revealed a required role of NRBF2 in modulating autophagosome maturation by interacting with Rab and Alzheimer disease-associated protein degradation [14]. Neuroinflammation and oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study is the first to show that activation of autophagy protein nuclear receptor binding factor 2 (NRBF2) could reduce endoplasmic reticulum stress (ERS)-associated inflammation and oxidative stress after SAH
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