TY - JOUR
T1 - Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis
AU - Shi, Bo
AU - Wang, Wenxia
AU - Korman, Benjamin
AU - Kai, Li
AU - Wang, Qianqian
AU - Wei, Jun
AU - Bale, Swarna
AU - Marangoni, Roberta Goncalves
AU - Bhattacharyya, Swati
AU - Miller, Stephen
AU - Xu, Dan
AU - Akbarpour, Mahzad
AU - Cheresh, Paul
AU - Proccissi, Daniele
AU - Gursel, Demirkan
AU - Espindola-Netto, Jair Machado
AU - Chini, Claudia C.S.
AU - de Oliveira, Guilherme C.
AU - Gudjonsson, Johann E.
AU - Chini, Eduardo N.
AU - Varga, John
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2021/1/22
Y1 - 2021/1/22
N2 - 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.
AB - 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.
KW - Human Metabolism
KW - Immunology
KW - Molecular Biology
UR - http://www.scopus.com/inward/record.url?scp=85098211189&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098211189&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101902
DO - 10.1016/j.isci.2020.101902
M3 - Article
AN - SCOPUS:85098211189
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 1
M1 - 101902
ER -