PMID- 34987507
OWN - NLM
STAT- MEDLINE
DCOM- 20220208
LR  - 20220208
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Intracellular NAD(+) Depletion Confers a Priming Signal for NLRP3 Inflammasome 
      Activation.
PG  - 765477
LID - 10.3389/fimmu.2021.765477 [doi]
LID - 765477
AB  - 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)-1beta 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-1beta 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.
CI  - Copyright (c) 2021 Shim, Cho, Hwang, Jung, Kim, Ryu and Yu.
FAU - Shim, Do-Wan
AU  - Shim DW
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Cho, Hyo-Joung
AU  - Cho HJ
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Hwang, Inhwa
AU  - Hwang I
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
FAU - Jung, Taek-Yeol
AU  - Jung TY
AD  - Department of Life Science, College of Natural Science, The Research Center for 
      Cellular Homeostasis, Ewha Womans University, Seoul, South Korea.
FAU - Kim, Hyun-Seok
AU  - Kim HS
AD  - Department of Life Science, College of Natural Science, The Research Center for 
      Cellular Homeostasis, Ewha Womans University, Seoul, South Korea.
FAU - Ryu, Ju Hee
AU  - Ryu JH
AD  - Theragnosis Research Center, Biomedical Research Division, Korea Institute of 
      Science and Technology (KIST), Seoul, South Korea.
FAU - Yu, Je-Wook
AU  - Yu JW
AD  - Department of Microbiology and Immunology, Institute for Immunology and 
      Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei 
      University College of Medicine, Seoul, South Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211220
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0U46U6E8UK (NAD)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Inflammasomes/*immunology
MH  - Macrophages/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - NAD/analysis/*immunology
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/deficiency/*immunology
PMC - PMC8722528
OTO - NOTNLM
OT  - NAD
OT  - aging
OT  - inflammasome
OT  - macrophage
OT  - proinflammatory
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/01/07 06:00
MHDA- 2022/02/09 06:00
PMCR- 2021/01/01
CRDT- 2022/01/06 05:53
PHST- 2021/08/27 00:00 [received]
PHST- 2021/12/03 00:00 [accepted]
PHST- 2022/01/06 05:53 [entrez]
PHST- 2022/01/07 06:00 [pubmed]
PHST- 2022/02/09 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.765477 [doi]
PST - epublish
SO  - Front Immunol. 2021 Dec 20;12:765477. doi: 10.3389/fimmu.2021.765477. eCollection 
      2021.