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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1469737
PKR Modulates Sterile Systemic Inflammation-Triggered Neuroinflammation and Brain Glucose Metabolism Disturbance
Provisionally accepted
Wai-Yin Cheng 1,2,3*
Xin-Zin Lee 3 Michael Siu-Lun Lai 3
Yuen Shan HO 4
Raymond Chuen-Chung Chang 3,5*- 1 Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, China
- 2 Research Institute for Future Food, Hong Kong Polytechnic University, Kowloon, Hong Kong, SAR China
- 3 School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
- 4 School of Nursing, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Kowloon, Hong Kong, SAR China
- 5 State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
Sterile systemic inflammation may contribute to neuroinflammation and accelerate the progression of neurodegenerative diseases. The double-stranded RNA-dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and inflammasome formation. This study aims to study the role of PKR in regulating sterile systemic inflammation-triggered neuroinflammation and cognitive dysfunctions. Here, the laparotomy mouse model was used to study neuroimmune responses triggered by sterile systemic inflammation. Our study revealed that genetic deletion of PKR in mice potently attenuated the laparotomy-induced peripheral and neural inflammation and cognitive deficits. Furthermore, intracerebroventricular injection of rAAV-DIO-PKR-K296R to inhibit PKR in cholinergic neurons of ChAT-IRES-Cre-eGFP mice rescued the laparotomy-induced changes in key metabolites of brain glucose metabolism, particularly the changes in phosphoenolpyruvate and succinate levels, and cognitive impairment in short-term and spatial working memory. Our results demonstrated the critical role of PKR in regulating neuroinflammation, brain glucose metabolism and cognitive dysfunctions in a peripheral inflammation model. PKR could be a novel pharmacological target for treating systemic inflammation-induced neuroinflammation and cognitive dysfunctions.
Keywords: Laparotomy1, microglia2, Neuroimmune responses3, Peripheral inflammation4, Postoperative cognitive dysfunction5, Protein kinase R6, Targeted metabolomics7
Received: 24 Jul 2024; Accepted: 06 Feb 2025.
Copyright: © 2025 Cheng, Lee, Lai, HO and Chang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wai-Yin Cheng, Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, China
Raymond Chuen-Chung Chang, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
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