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Link to original content: https://pubmed.ncbi.nlm.nih.gov/37940045/
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Review
. 2024 Feb;47(1):100677.
doi: 10.1016/j.bj.2023.100677. Epub 2023 Nov 7.

Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review

Helena Neudorf  1 , Jonathan P Little  2
Affiliations
Review

Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review

Helena Neudorf et al. Biomed J. 2024 Feb.

Abstract

Overactivation of the NLRP3 inflammasome is implicated in chronic low-grade inflammation associated with various disease states, including obesity, type 2 diabetes, atherosclerosis, Alzheimer's disease, and Parkinson's disease. Emerging evidence, mostly from cell and animal models of disease, supports a role for ketosis in general, and the main circulating ketone body beta-hydroxybutyrate (BHB) in particular, in reducing NLRP3 inflammasome activation to improve chronic inflammation. As a result, interventions that can induce ketosis (e.g., fasting, intermittent fasting, time-restricted feeding/eating, very low-carbohydrate high-fat ketogenic diets) and/or increase circulating BHB (e.g., exogenous ketone supplementation) have garnered increasing interest for their therapeutic potential. The purpose of the present review is to summarize our current understanding of the literature on how ketogenic interventions impact the NLRP3 inflammasome across human, rodent and cell models. Overall, there is convincing evidence that ketogenic interventions, likely acting through multiple interacting mechanisms in a cell-, disease- and context-specific manner, can reduce NLRP3 inflammasome activation. The evidence supports a direct effect of BHB, although it is important to consider the myriad of other metabolic responses to fasting or ketogenic diet interventions (e.g., elevated lipolysis, low insulin, stable glucose, negative energy balance) that may also impact innate immune responses. Future research is needed to translate promising findings from discovery science to clinical application.

Keywords: Beta-hydroxybutyrate; Fasting; Inflammation; Ketogenic diets; NLRP3 inflammasome.

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Figures

Fig. 1
Fig. 1
Mechanistic overview of NLRP3 inflammasome signalling. Abbreviations:ASC: associated speck-like protein; CARD: caspase activation and recruitment domain; FADD:Fas-associated death domain protein; IKK:IkB kinase; IL: interleukin; LPS: lipopolysaccharide; MyD88: myeloid differentiation primary response 88; NACHT: NAIP (neuronal apoptosis inhibitor protein), C2TA (class 2 transcription activator, of the MHC), HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1); Nek7: never in mitosis gene A (NIMA)-related kinase; NF-kB: nuclear factor k-light-chain-enhancer of activated B cells; NLRP3:NOD-like receptor pyrin domain containing 3; PYD: pyrin domain; LRR: C-terminal receptor domain of leucine-rich repeats; RIPK1: receptor-interacting serine/threonine-protein kinase 1; TLR4: toll-like receptor 4; TRIF: toll-interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta.
Fig. 2
Fig. 2
The NLRP3 inflammasome as a central mediator of disease. AT, adipose tissue; NLRP3, NOD-like receptor pyrin domain containing 3; oxLDL, oxidized low-density lipoprotein; IAPP, islet amyloid polypeptide. Abbreviations:AT: adipose tissue; IAPP: islet amyloid polypeptide; NLRP3: NOD-like receptor pyrin domain containing 3; oxLDL: oxidized low-density lipoprotein.
Fig. 3
Fig. 3
Major metabolic perturbations and differences of endogenous versus exogenous ketogenic interventions. Abbreviations: AcAc: acetoacetate; D-BHB: D-isoform of beta-hydroxybutyrate; FFA: free fatty acid; GH: growth hormone; GPR109A: G protein-coupled receptor 109A.
Fig. 4
Fig. 4
Depiction of recently-characterized mechanisms of BHB-mediated suppression of NLRP3 inflammasome activation. Abbreviations: AMPK: 5' AMP-activated protein kinase; ASC: associated speck-like protein; ATF6a: activating transcription factor 6 a; ER: endoplasmic reticulum; Foxo3a: forkhead box O3a; HDAC: histone deacetylase; IL: interleukin; IRE1: phosphorylated inositol-requiring enzyme 1; Mn-SOD: manganese superoxide dismutase; Mt2: metallothionein 2; Nek7: never in mitosis gene A (NIMA)-related kinase; NLRP3: NOD-like receptor (NLR) family pyrin domain containing 3; PERK: protein kinase R (PKR)-like endoplasmic reticulum kinase; ROS: reactive oxygen species; TXNIP: thioredoxin-interacting protein.
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