Shi Bo, Wang Wenxia, Korman Benjamin, Kai Li, Wang Qianqian, Wei Jun, Bale Swarna, Marangoni Roberta Goncalves, Bhattacharyya Swati, Miller Stephen, Xu Dan, Akbarpour Mahzad, Cheresh Paul, Proccissi Daniele, Gursel Demirkan, Espindola-Netto Jair Machado, Chini Claudia C S, de Oliveira Guilherme C, Gudjonsson Johann E, Chini Eduardo N, Varga John
Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
iScience. 2020 Dec 7;24(1):101902. doi: 10.1016/j.isci.2020.101902. eCollection 2021 Jan 22.
The processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD) that is due to dysregulation of NAD homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD-synthesizing enzymes is unaltered. Boosting NAD via genetic or pharmacological CD38 targeting or NAD precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. In mechanistic experiments, CD38 was found to reduce NAD levels and sirtuin activity to augment cellular fibrotic responses, while inhibiting CD38 had the opposite effect. Thus, we identify CD38 upregulation and resulting disrupted NAD homeostasis as a fundamental mechanism driving fibrosis in SSc, suggesting that CD38 might represent a novel therapeutic target.
系统性硬化症（SSc）中同步性多器官纤维化的潜在机制仍知之甚少。与年龄相关的病理状况与烟酰胺腺嘌呤二核苷酸（NAD）的机体水平下降有关，这是由于NAD稳态失调所致，且涉及NAD酶CD38。我们现在发现，弥漫性皮肤型SSc患者的CD38表达上调，皮肤中的CD38水平与分子纤维化特征以及临床纤维化评分相关，而关键NAD合成酶的表达未发生改变。通过基因或药物靶向CD38或补充NAD前体来提高NAD水平，可保护小鼠免受皮肤、肺部和腹膜纤维化的影响。在机制实验中，发现CD38会降低NAD水平和去乙酰化酶活性，从而增强细胞纤维化反应，而抑制CD38则产生相反的效果。因此，我们确定CD38上调以及由此导致的NAD稳态破坏是驱动SSc纤维化的一个基本机制，这表明CD38可能是一个新的治疗靶点。
