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

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Abstract

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.

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Abbreviations

βOHB:

β-hydroxybutyrate

Arg 1:

Arginase 1

ASC:

apoptosis-associated speck-like protein containing a caspase-1 recruitment domain

EC:

Eriochrome cyanine

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

iNOS:

inducible nitric oxide synthase

IL-1β:

Interleukin 1β

KD:

Ketogenic diet

LPS:

Lipopolysaccharide

NLRP3:

Nucleotide oligomerization domain-like receptor family, pyrin domain containing 3

PBS:

phosphate-buffered saline

SCI:

Spinal cord injury

SD:

Standard diet

SSEPs:

Somatosensory-evoked potentials

TcMEPs:

Transcranial motor-evoked potentials

TNF-α:

Tumor necrosis factor alpha

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Funding

This study was supported by grants from the National Natural Science Foundation of China (81472084 and 81601904), the China Postdoctoral Science Foundation (2018M643328) and the Natural Science Foundation of Guangdong Province (2016A030313553).

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Authors and Affiliations

  1. Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China

    Ganggang Kong, Junhao Liu, Rong Li, Junyu Lin, Zucheng Huang, Zhou Yang, Xiuhua Wu, Zhiping Huang, Qingan Zhu & Xiaoliang Wu

  2. Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Ganggang Kong

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Contributions

Ganggang Kong, Junhao Liu, Rong Li, Zucheng Huang, Zhou Yang, Junyu Lin, Xiuhua Wu and Zhiping Huang performed the experiments; Xiaoliang Wu and Qingan Zhu designed the study; and Ganggang Kong and Xiaoliang Wu wrote the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Qingan Zhu or Xiaoliang Wu.

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Kong, G., Liu, J., Li, R. et al. Ketone Metabolite β-Hydroxybutyrate Ameliorates Inflammation After Spinal Cord Injury by Inhibiting the NLRP3 Inflammasome. Neurochem Res 46, 213–229 (2021). https://doi.org/10.1007/s11064-020-03156-2

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