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

IF 4.8 3区 医学 Q2 CELL BIOLOGY
Inflammation Research Pub Date : 2024-05-01 Epub Date: 2024-03-16 DOI:10.1007/s00011-024-01863-y
Paulo Gil Alabarse, Patricia Oliveira, Huaping Qin, Tiffany Yan, Marie Migaud, Robert Terkeltaub, Ru Liu-Bryan
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引用次数: 0

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.

NAD 酶 CD38 是痛风性炎症的核心调节因子,也是一种新型药物治疗靶点。
目的:细胞中的 NAD+ 在炎症状态下会减少,同时白细胞表达的 NAD 酶 CD38 的活性也会增加。在这项研究中,我们测试了以 CD38 和 NAD+ 为治疗靶点在痛风中的潜在作用:我们研究了在单钠尿酸盐(MSU)结晶刺激下培养的小鼠野生型和 CD38 基因敲除(KO)小鼠骨髓衍生巨噬细胞(BMDMs),并使用气囊痛风炎症模型:结果:MSU 晶体在体外诱导 BMDMs 中的 CD38,与 NAD+ 耗竭、IL-1β 和 CXCL1 释放有关,药物 CD38 抑制剂(芹菜素、78c)可逆转这些效应。CD38 KO 和芹菜素能减弱小鼠气囊对 MSU 晶体的炎症反应。药物 CD38 抑制剂抑制了 MSU 晶体诱导的 NLRP3 炎性体活化,并提高了巨噬细胞中抗炎性 SIRT3-SOD2 的活性。BMDM差异表达基因(DEGs)的RNA-seq分析显示,CD38控制着多种由MSU晶体调控的炎症通路。最主要的 DEGs 包括昼夜节律调节因子 GRP176 和金属还原酶 STEAP4,后者介导铁的稳态,并在过度表达时促进氧化应激和 NF-κB 的活化:结论:CD38和NAD+消耗是控制MSU晶体诱导的炎症程序的药物靶点。以CD38和NAD+为靶点可能是限制痛风性关节炎的新型选择性分子方法。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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