VA San Diego Healthcare System, 111K, 3350 La Jolla Village Drive, San Diego, CA, 92161, USA.
University of California San Diego, La Jolla, San Diego, CA, USA.
Inflamm Res. 2024 May;73(5):739-751. doi: 10.1007/s00011-024-01863-y. Epub 2024 Mar 16.
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.
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.
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.
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.
细胞内 NAD 水平会在与白细胞表达的 NAD 水解酶 CD38 活性增加相关的炎症状态下下降。在这项研究中，我们测试了靶向治疗 CD38 和 NAD 在痛风中的潜在作用。
我们研究了培养的野生型和 CD38 敲除（KO）鼠骨髓来源巨噬细胞（BMDM），这些细胞受到尿酸单钠（MSU）晶体的刺激，并使用气囊痛风性炎症模型。
MSU 晶体在体外诱导 BMDM 中的 CD38，伴随着 NAD 的消耗，以及 IL-1β 和 CXCL1 的释放，这些效应可被药理学 CD38 抑制剂（芹菜素，78c）逆转。MSU 晶体对小鼠气囊炎症反应的抑制作用可被 CD38 KO 和芹菜素减弱。药理学 CD38 抑制抑制了 MSU 晶体诱导的 NLRP3 炎性小体激活，并增加了巨噬细胞中的抗炎 SIRT3-SOD2 活性。BMDM 的 RNA-seq 分析显示差异表达基因（DEGs）受 CD38 调控，这些基因调控多个 MSU 晶体调节的炎症途径。顶级 DEGs 包括昼夜节律调节剂 GRP176 和金属还原酶 STEAP4，当它过表达时，STEAP4 介导铁稳态，并促进氧化应激和 NF-κB 激活。
CD38 和 NAD 的消耗是可调控的靶点，控制着 MSU 晶体诱导的炎症程序。靶向 CD38 和 NAD 是限制痛风性关节炎的潜在新型选择性分子方法。
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