PMID- 38493256
OWN - NLM
STAT- MEDLINE
DCOM- 20240429
LR  - 20240503
IS  - 1420-908X (Electronic)
IS  - 1023-3830 (Print)
IS  - 1023-3830 (Linking)
VI  - 73
IP  - 5
DP  - 2024 May
TI  - The NADase CD38 is a central regulator in gouty inflammation and a novel 
      druggable therapeutic target.
PG  - 739-751
LID - 10.1007/s00011-024-01863-y [doi]
AB  - OBJECTIVES: Cellular NAD(+) declines in inflammatory states associated with 
      increased activity of the leukocyte-expressed NADase CD38. In this study, we 
      tested the potential role of therapeutically targeting CD38 and NAD(+) in gout. 
      METHODS: We studied cultured mouse wild type and CD38 knockout (KO) murine bone 
      marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals 
      and used the air pouch gouty inflammation model. RESULTS: MSU crystals induced 
      CD38 in BMDMs in vitro, associated with NAD(+) depletion, and IL-1beta and CXCL1 
      release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse 
      air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and 
      apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 
      inflammasome activation and increased anti-inflammatory SIRT3-SOD2 activity in 
      macrophages. BMDM RNA-seq analysis of differentially expressed genes (DEGs) 
      revealed CD38 to control multiple MSU crystal-modulated inflammation pathways. 
      Top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase 
      STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-kappaB 
      activation when it is overexpressed. CONCLUSIONS: CD38 and NAD(+) depletion are 
      druggable targets controlling the MSU crystal- induced inflammation program. 
      Targeting CD38 and NAD(+) are potentially novel selective molecular approaches to 
      limit gouty arthritis.
CI  - (c) 2024. This is a U.S. Government work and not under copyright protection in the 
      US; foreign copyright protection may apply.
FAU - Alabarse, Paulo Gil
AU  - Alabarse PG
AD  - VA San Diego Healthcare System, 111K, 3350 La Jolla Village Drive, San Diego, CA, 
      92161, USA.
FAU - Oliveira, Patricia
AU  - Oliveira P
AD  - University of California San Diego, La Jolla, San Diego, CA, USA.
AD  - The Janssen Pharmaceutical Companies of Johnson & Johnson, La Jolla, San Diego, 
      CA, USA.
FAU - Qin, Huaping
AU  - Qin H
AD  - University of California San Diego, La Jolla, San Diego, CA, USA.
FAU - Yan, Tiffany
AU  - Yan T
AD  - University of California San Diego, La Jolla, San Diego, CA, USA.
AD  - Gritstone Bio, Emeryville, CA, USA.
FAU - Migaud, Marie
AU  - Migaud M
AD  - Department of Pharmacology, F. Whiddon College of Medicine, Mitchell Cancer 
      Institute, University of South Alabama, Mobile, AL, 36604, USA.
FAU - Terkeltaub, Robert
AU  - Terkeltaub R
AD  - VA San Diego Healthcare System, 111K, 3350 La Jolla Village Drive, San Diego, CA, 
      92161, USA.
AD  - University of California San Diego, La Jolla, San Diego, CA, USA.
FAU - Liu-Bryan, Ru
AU  - Liu-Bryan R
AUID- ORCID: 0000-0002-9611-8163
AD  - VA San Diego Healthcare System, 111K, 3350 La Jolla Village Drive, San Diego, CA, 
      92161, USA. ruliu@ucsd.edu.
AD  - University of California San Diego, La Jolla, San Diego, CA, USA. ruliu@ucsd.edu.
LA  - eng
GR  - I01 BX002234/BX/BLRD VA/United States
PT  - Journal Article
DEP - 20240316
PL  - Switzerland
TA  - Inflamm Res
JT  - Inflammation research : official journal of the European Histamine Research 
      Society ... [et al.]
JID - 9508160
RN  - EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
RN  - EC 3.2.2.5 (Cd38 protein, mouse)
RN  - 268B43MJ25 (Uric Acid)
RN  - 0U46U6E8UK (NAD)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Inflammasomes)
SB  - IM
MH  - Animals
MH  - *ADP-ribosyl Cyclase 1/genetics/metabolism
MH  - *Mice, Knockout
MH  - *Macrophages/drug effects/metabolism
MH  - *Mice, Inbred C57BL
MH  - *Inflammation/drug therapy
MH  - *Uric Acid
MH  - Mice
MH  - *NAD/metabolism
MH  - Membrane Glycoproteins/genetics/metabolism
MH  - Male
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
MH  - Cells, Cultured
MH  - Arthritis, Gouty/drug therapy/metabolism/genetics
MH  - Inflammasomes/metabolism/drug effects
PMC - PMC11058052
OTO - NOTNLM
OT  - CD38
OT  - Gout
OT  - Inflammation
OT  - Macrophages
OT  - NAD+
COIS- The authors have no conflict of interest declare that are relevant to the content 
      of this article.
EDAT- 2024/03/17 06:42
MHDA- 2024/04/29 13:57
PMCR- 2024/03/16
CRDT- 2024/03/17 00:27
PHST- 2023/10/17 00:00 [received]
PHST- 2024/02/13 00:00 [accepted]
PHST- 2024/01/23 00:00 [revised]
PHST- 2024/04/29 13:57 [medline]
PHST- 2024/03/17 06:42 [pubmed]
PHST- 2024/03/17 00:27 [entrez]
PHST- 2024/03/16 00:00 [pmc-release]
AID - 10.1007/s00011-024-01863-y [pii]
AID - 1863 [pii]
AID - 10.1007/s00011-024-01863-y [doi]
PST - ppublish
SO  - Inflamm Res. 2024 May;73(5):739-751. doi: 10.1007/s00011-024-01863-y. Epub 2024 
      Mar 16.