WNK1 Alleviates Chloride Efflux-Induced NLRP3 Inflammasome Activation and Subsequent Neuroinflammation in Early Brain Injury Following Subarachnoid Hemorrhage.
10.1007/s12264-025-01414-3
- Author:
Panpan ZHAO
1
;
Huimiao FENG
2
;
Xinyu ZHOU
3
;
Jingyuan ZHOU
1
;
Fangbo HU
1
;
Taotao HU
1
;
Yong SUN
4
Author Information
1. Neurosurgery Department, Institute of Neuroscience, Lianyungang Clinical College of Nanjing Medical University, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, 222000, China.
2. Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
3. Department of Neurology, Institute of Neuroscience, Lianyungang Clinical College of Nanjing Medical University, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, 222000, China.
4. Neurosurgery Department, Institute of Neuroscience, Lianyungang Clinical College of Nanjing Medical University, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, 222000, China. sunyong@njmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Chloride;
NLRP3 inflammasome;
Neuroinflammation;
P2X7R;
Subarachnoid hemorrhage;
WNK1
- MeSH:
Animals;
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism*;
Subarachnoid Hemorrhage/complications*;
Inflammasomes/metabolism*;
Rats;
Mice;
Neuroinflammatory Diseases/metabolism*;
WNK Lysine-Deficient Protein Kinase 1/genetics*;
Male;
Humans;
Chlorides/metabolism*;
Mice, Inbred C57BL;
Rats, Sprague-Dawley;
Brain Injuries/metabolism*;
Microglia/metabolism*;
Protein Serine-Threonine Kinases
- From:
Neuroscience Bulletin
2025;41(9):1570-1588
- CountryChina
- Language:English
-
Abstract:
The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
