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Inflammation Research
Published in: Inflammation Research 5/2024

Open Access 16-03-2024 | Gout | Original Research Paper

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

Authors: Paulo Gil Alabarse, Patricia Oliveira, Huaping Qin, Tiffany Yan, Marie Migaud, Robert Terkeltaub, Ru Liu-Bryan

Published in: Inflammation Research | Issue 5/2024

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Abstract

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.
Appendix
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Literature
1.
2.
3.
4.
Cipolletta E, Tata LJ, Nakafero G, Avery AJ, Mamas MA, Abhishek A. Association between gout flare and subsequent cardiovascular events among patients with gout. JAMA. 2022;328:440–50.PubMedPubMedCentralCrossRef
5.
Martin WJ, Walton M, Harper J. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis Rheum. 2009;60:281–9.PubMedCrossRef
6.
7.
Cronstein BN, Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013;19:19–29.PubMedPubMedCentralCrossRef
8.
9.
Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD (+) metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021;22:119–41.PubMedCrossRef
10.
Zeidler JD, Hogan KA, Agorrody G, Peclat TR, Kashyap S, Kanamori KS, et al. The CD38 glycohydrolase and the NAD sink: implications for pathological conditions. Am J Physiol Cell Physiol. 2022;322:C521–45.PubMedPubMedCentralCrossRef
11.
He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, et al. An Acetylation switch of the nlrp3 inflammasome regulates aging-associated chronic inflammation and insulin resistance. Cell Metab. 2020;31:580-591.e5.PubMedPubMedCentralCrossRef
12.
Shim DW, Cho HJ, Hwang I, Jung TY, Kim HS, Ryu JH, et al. Intracellular NAD+ depletion confers a priming signal for NLRP3 inflammasome activation. Front Immunol. 2021;12: 765477.PubMedPubMedCentralCrossRef
13.
Aksoy P, White TA, Thompson M, Chini EN. Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun. 2006;345:1386–92.PubMedCrossRef
14.
Piedra-Quintero ZL, Wilson Z, Nava P, Guerau-de-Arellano M. CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front Immunol. 2020;30(11): 597959.CrossRef
15.
16.
Amici SA, Young NA, Narvaez-Miranda J, Jablonski KA, Arcos J, Rosas L, et al. CD38 is robustly induced in human macrophages and monocytes in inflammatory conditions. Front Immunol. 2018;9:1593.PubMedPubMedCentralCrossRef
17.
Wen S, Arakawa H, Tamai I. CD38 activation by monosodium urate crystals contributes to inflammatory responses in human and murine macrophages. Biochem Biophys Res Commun. 2021;581:6–11.PubMedCrossRef
18.
Liu L, Zhu X, Zhao T, Yu Y, Xue Y, Zou H. Sirt1 ameliorates monosodium urate crystal-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway. Rheumatology (Oxford). 2019;58:1674–83.PubMedCrossRef
19.
Wang J, Chen G, Lu L, Zou H. Sirt1 inhibits gouty arthritis via activating PPARγ. Clin Rheumatol. 2019;38:3235–42.PubMedCrossRef
20.
Edwards JC, Sedgwick AD, Willoughby DA. The formation of a structure with the features of synovial lining by subcutaneous injection of air: an in vivo tissue culture system. J Pathol. 1981;134:147–56.PubMedCrossRef
21.
Pessler F, Mayer CT, Jung SM, Behrens EM, Dai L, Menetski JP, Schumacher HR. Identification of novel monosodium urate crystal regulated mRNAs by transcript profiling of dissected murine air pouch membranes. Arthritis Res Ther. 2008;10:R64.PubMedPubMedCentralCrossRef
22.
Wu J, Jin Z, Zheng H, Yan LJ. Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications. Diabetes Metab Syndr Obes. 2016;9:145–53.PubMedPubMedCentral
23.
Amjad S, Nisar S, Bhat AA, Shah AR, Frenneaux MP, Fakhro K, et al. Role of NAD+ in regulating cellular and metabolic signaling pathways. Mol Metab. 2021;49: 101195.PubMedPubMedCentralCrossRef
24.
Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, et al. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes. 2013;62:1084–93.PubMedPubMedCentralCrossRef
25.
26.
Ozden O, Park SH, Kim HS, Jiang H, Coleman MC, Spitz DR, et al. Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging (Albany NY). 2011;3:102–7.PubMedCrossRef
27.
Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28:1717-1728.e6.PubMedPubMedCentralCrossRef
28.
Zhou B, Wang DD, Qiu Y, Airhart S, Liu Y, Stempien-Otero A, et al. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J Clin Invest. 2020;130:6054–63.PubMedPubMedCentralCrossRef
29.
Wu J, Singh K, Lin A, Meadows AM, Wu K, Shing V, et al. Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes. J Clin Invest. 2022;132: e139828.PubMedPubMedCentralCrossRef
30.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.PubMedCrossRef
31.
Zhang Z, Xu HN, Li S Jr, AD, Chellappa K, Davis JG, et al. Rapamycin maintains NAD+/NADH redox homeostasis in muscle cells. Aging (Albany NY). 2020;12:17786–99.PubMedCrossRef
32.
Teodoro JS, Rolo AP, Palmeira CM. The NAD ratio redox paradox: why does too much reductive power cause oxidative stress? Toxicol Mech Methods. 2013;23:297–302.PubMedCrossRef
33.
34.
Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14:454–60.PubMedCrossRef
35.
Traba J, Geiger SS, Kwarteng-Siaw M, Han K, Ra OH, Siegel RM, et al. Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and activation via SIRT3-mediated activation of superoxide dismutase 2. J Biol Chem. 2017;292:12153–64.PubMedPubMedCentralCrossRef
36.
Zheng J, Shi L, Liang F, Xu W, Li T, Gao L, et al. Sirt3 ameliorates oxidative stress and mitochondrial dysfunction after intracerebral hemorrhage in diabetic rats. Front Neurosci. 2018;12:414.PubMedPubMedCentralCrossRef
37.
Dong X, He Y, Ye F, Zhao Y, Cheng J, Xiao J, et al. Vitamin D3 ameliorates nitrogen mustard-induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. Clin Transl Med. 2021;11: e312.PubMedPubMedCentralCrossRef
38.
Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012;10(109):11282–7.CrossRef
39.
Li JP, Wei W, Li XX, Xu M. Regulation of NLRP3 inflammasome by CD38 through cADPR-mediated Ca2+ release in vascular smooth muscle cells in diabetic mice. Life Sci. 2020;255: 117758.PubMedCrossRef
40.
Wang Z, Zhao Y, Phipps-Green A, Liu-Bryan R, Ceponis A, Boyle DL, et al. Differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways in gout. Arthritis Rheumatol. 2020;72:802–14.PubMedPubMedCentralCrossRef
41.
Scarl RT, Lawrence CM, Gordon HM, Nunemaker CS. STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper. J Endocrinol. 2017;234:R123–34.PubMedPubMedCentralCrossRef
42.
Liao Y, Zhao J, Bulek K, Tang F, Chen X, Cai G, et al. Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis. Nat Commun. 2020;11:900.PubMedPubMedCentralCrossRef
43.
Xue X, Bredell BX, Anderson ER, Martin A, Mays C, Nagao-Kitamoto H, et al. Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer. Proc Natl Acad Sci U S A. 2017;114:E9608–17.PubMedPubMedCentralCrossRef
44.
45.
McWherter C, Choi YJ, Serrano RL, Mahata SK, Terkeltaub R, Liu-Bryan R. Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling. Arthritis Res Ther. 2018;20:204.PubMedPubMedCentralCrossRef
46.
Zhou J, Ye S, Fujiwara T, Manolagas SC, Zhao H. Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB)activation. J Biol Chem. 2013;288:30064–74.PubMedPubMedCentralCrossRef
47.
Dalbeth N, Smith T, Nicolson B, Clark B, Callon K, Naot D, et al. Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells. Arthritis Rheum. 2008;58:1854–65.PubMedCrossRef
48.
Gold ES, Diercks AH, Podolsky I, Podyminogin RL, Askovich PS, Treuting PM, et al. 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc Natl Acad Sci U S A. 2014;111:10666–71.PubMedPubMedCentralCrossRef
49.
50.
Taye A, El-Sheikh AA. Lectin-like oxidized low-density lipoprotein receptor 1 pathways. Eur J Clin Invest. 2013;43:740–5.PubMedCrossRef
51.
Doi M, Murai I, Kunisue S, Setsu G, Uchio N, Tanaka R, et al. Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour. Nat Commun. 2016;7:10583.PubMedPubMedCentralCrossRef
52.
Nathan P, Gibbs JE, Rainger GE, Chimen M. Changes in circadian rhythms dysregulate inflammation in ageing: focus on leukocyte trafficking. Front Immunol. 2021;12: 673405.PubMedPubMedCentralCrossRef
53.
54.
Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun. 2018;9:1286.PubMedPubMedCentralCrossRef
55.
Dellinger RW, Santos SR, Morris M, Evans M, Alminana D, Guarente L, et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis. 2017;3:17.PubMedPubMedCentralCrossRef
Metadata
Title
The NADase CD38 is a central regulator in gouty inflammation and a novel druggable therapeutic target
Authors
Paulo Gil Alabarse
Patricia Oliveira
Huaping Qin
Tiffany Yan
Marie Migaud
Robert Terkeltaub
Ru Liu-Bryan
Publication date
16-03-2024
Publisher
Springer International Publishing
Keyword
Gout
Published in
Inflammation Research / Issue 5/2024
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-024-01863-y

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