Ketone Metabolite β-Hydroxybutyrate Ameliorates Inflammation After Spinal Cord Injury by Inhibiting the NLRP3 Inflammasome

• Published in: Neurochemical research 2021-02, Vol.46 (2), p.213-229
• Main Authors: Kong, Ganggang, Liu, Junhao, Li, Rong, Lin, Junyu, Huang, Zucheng, Yang, Zhou, Wu, Xiuhua, Huang, Zhiping, Zhu, Qingan, Wu, Xiaoliang
• Format: Article
• Language: English
• Subjects: 3-Hydroxybutyric Acid - metabolism; 3-Hydroxybutyric Acid - therapeutic use; Adenosine triphosphate; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cell activation; Cell Biology; Cell Line; Cytokines; Cytokines - metabolism; Diet; Diet, Ketogenic; Domains; Down-Regulation; Genotype & phenotype; High fat diet; In vivo methods and tests; Inflammasomes; Inflammasomes - drug effects; Inflammation; Inflammation - drug therapy; Inflammation - etiology; Inflammation - metabolism; Inflammation - prevention & control; Inflammatory response; Ketogenesis; Ketones; Lipopolysaccharides; Low carbohydrate diet; Macrophage Activation - drug effects; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Metabolites; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Neurochemistry; Neurological diseases; Neurology; Neuroprotection - drug effects; Neurosciences; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotides; Oligomerization; Original Paper; Phenotypes; Pyrin protein; Rats; Rats, Sprague-Dawley; Spinal cord injuries; Spinal Cord Injuries - complications; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - prevention & control
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-020-03156-2

Ketogenic diet (KD) has been shown to be beneficial in a range of neurological disorders, with ketone metabolite β-hydroxybutyrate (βOHB) reported to block the nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in bone marrow-derived macrophages. In this study, we show that pretreatment with KD or in situ βOHB suppressed macrophages/microglia activation and the overproduction of inflammatory cytokines, while KD downregulated the expression of NLRP3 inflammasome. Moreover, KD promoted macrophages/microglia transformation from the M1 phenotype to the M2a phenotype following spinal cord injury (SCI) in the in vivo study. Rats in the KD group demonstrated improved behavioral and electrophysiological recovery after SCI when compared to those rats in the standard diet group. The in vitro study performed on BV2 cells indicated that βOHB inhibited an LPS+ATP-induced inflammatory response and decreased NLRP3 protein levels. Our data demonstrated that pretreatment with KD attenuated neuroinflammation following SCI, probably by inhibiting NLRP3 inflammasome and shifting the activation state of macrophages/microglia from the M1 to the M2a phenotype. Therefore, the ketone metabolite βOHB might provide a potential future therapeutic strategy for SCI.