95 175

Cited 0 times in

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

Authors
 Do-Wan Shim  ;  Hyo-Joung Cho  ;  Inhwa Hwang  ;  Taek-Yeol Jung  ;  Hyun-Seok Kim  ;  Ju Hee Ryu  ;  Je-Wook Yu 
Citation
 FRONTIERS IN IMMUNOLOGY, Vol.12 : 765477, 2021-12 
Journal Title
FRONTIERS IN IMMUNOLOGY
Issue Date
2021-12
MeSH
Animals ; Cells, Cultured ; Inflammasomes / immunology* ; Macrophages / immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; NAD / analysis ; NAD / immunology* ; NLR Family, Pyrin Domain-Containing 3 Protein / deficiency ; NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
Keywords
NAD ; aging ; inflammasome ; macrophage ; proinflammatory
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.
Files in This Item:
T202125136.pdf Download
DOI
10.3389/fimmu.2021.765477
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Others (기타) > 1. Journal Papers
Yonsei Authors
Shim, Do-Wan(심도완)
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
Hwang, Inhwa(황인화) ORCID logo https://orcid.org/0000-0001-5235-3519
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187700
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links