NDLI: Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors

Content Provider	Springer Nature : BioMed Central
Author	Chen, Yuxin Li, Xiaohuan Xiong, Qian Du, Yehong Luo, Man Yi, Lilin Pang, Yayan Shi, Xiuyu Wang, Yu Tian Dong, Zhifang
Abstract	Background The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear. Methods The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1β (IL-1β), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM). Results We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1β, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1. Conclusion Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy.
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-023-04452-5.pdf
Ending Page	18
Page Count	18
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-023-04452-5
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	21
Language	English
Publisher	BioMed Central
Publisher Date	2023-08-24
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health Hypoxic-ischemic brain damage NLRP3 Caspase-1 GluA1 p97 Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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