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Cited by 24Inflammasome and immune disordersImmune Response and InflammationSirtuins and Resveratrol in Medicine

Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation

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Shim, Do-Wan, Cho, Hyo-Joung, Hwang, Inhwa, Jung, Taek-Yeol, Kim, Hyun-Seok, Ryu, Ju Hee, Yu, Je-Wook·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.765477PMC PMC8722528
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Abstract

Nicotinamide adenine dinucleotide (NAD+) is an important cofactor in many redox and non-redox NAD+-consuming enzyme reactions. Intracellular NAD+ level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD+ depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages. NAD+-depleted mouse bone marrow-derived macrophages (BMDMs) exhibited similar levels of proinflammatory cytokine production in response to LPS or poly (I:C) stimulation compared with untreated cells. Instead, FK866 facilitated robust caspase-1 activation in BMDMs in the presence of NLRP3-activating signals such as ATP and nigericin, a potassium ionophore. However, this FK866-mediated caspase-1 activation was completely abolished in Nlrp3-deficient macrophages. FK866 plus nigericin stimulation caused an NLRP3-dependent assembly of inflammasome complex. In contrast, restoration of NAD+ level by supplementation with nicotinamide mononucleotide abrogated the FK866-mediated caspase-1 cleavage. FK866 did not induce or increase the expression levels of NLRP3 and interleukin (IL)-1β but drove mitochondrial retrograde transport into the perinuclear region. FK866-nigericin-induced mitochondrial transport is critical for caspase-1 cleavage in macrophages. Consistent with the in vitro experiments, intradermal coinjection of FK866 and ATP resulted in robust IL-1β expression and caspase-1 activation in the skin of wild-type, but not Nlrp3-deficient mice. Collectively, our data suggest that NAD+ depletion provides a non-transcriptional priming signal for NLRP3 activation via mitochondrial perinuclear clustering, and aging-associated NAD+ decline can trigger NLRP3 inflammasome activation in ATP-rich environments.

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  • NLRP3 inflammasome activation increases glycolytic metabolites such as fructose 1,6-biphosphate via PFK-1 and reduces NAD, with no change in cystine or betaine.

    “NLRP3 inflammasome activation also increased glycolytic metabolites45 such as fructose 1, 6-biphosphate via phosphofructokinase-1,46 alongside reduced nicotinamide adenine dinucleotide (NAD) (Figure 2A), a key cofactor in redox reactions,47 with no change in cystine (the oxidized dimeric form of cysteine) or betaine, an organic osmolyte in the methionine cycle (Figures 2B and Figure S2C).”

    From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [47]

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Authors
Shim, D.-W., Cho, H.-J., Hwang, I., Jung, T.-Y., Kim, H.-S., Ryu, J. H., & Yu, J.-W.
Affiliations
  • Yonsei University (KR)
  • Ewha Womans University (KR)
  • Korea Institute of Science and Technology (KR)
Corresponding author
Yu, Je-Wook
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-12-20
Volume
12
Pages
765477-765477
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.765477
PMC
PMC8722528
OpenAlex
W4200528937
Cited by
24
References
7
Citations by year
2026: 6 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 1
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
National Research Foundation of Korea (2020R1A2B5B02001823, 2020R1A4A1019009, 2019R1I1A1A01060316, 2021R1I1A1A01055624)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
NAD+ depletion, NLRP3 inflammasome, caspase-1 activation, FK866, NAD+ salvage pathway, macrophages, IL-1β, aging, ATP, nigericin, innate immunity, inflammasome priming
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cells, Cultured, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, NAD, Mice, Knockout, Mice, Inflammasomes

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