The NADase CD38 is a central regulator in gouty inflammation and a novel druggable therapeutic target

© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..

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-1β 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-κB 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.

Medienart:

E-Artikel

Erscheinungsjahr:

2024

Erschienen:

2024

Enthalten in:

Zur Gesamtaufnahme - year:2024

Enthalten in:

Inflammation research : official journal of the European Histamine Research Society ... [et al. - (2024) vom: 16. März

Sprache:

Englisch

Beteiligte Personen:

Alabarse, Paulo Gil [VerfasserIn]
Oliveira, Patricia [VerfasserIn]
Qin, Huaping [VerfasserIn]
Yan, Tiffany [VerfasserIn]
Migaud, Marie [VerfasserIn]
Terkeltaub, Robert [VerfasserIn]
Liu-Bryan, Ru [VerfasserIn]

Links:

Volltext

Themen:

CD38
Gout
Inflammation
Journal Article
Macrophages
NAD+

Anmerkungen:

Date Revised 17.03.2024

published: Print-Electronic

Citation Status Publisher

doi:

10.1007/s00011-024-01863-y

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM369829352