Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis

Bo Shi, Wenxia Wang, Benjamin Korman, Li Kai, Qianqian Wang, Jun Wei, Swarna Bale, Roberta Goncalves Marangoni, Swati Bhattacharyya, Stephen Miller, Dan Xu, Mahzad Akbarpour, Paul Cheresh, Daniele Proccissi, Demirkan Gursel, Jair Machado Espindola-Netto, Claudia C.S. Chini, Guilherme C. de Oliveira, Johann E. Gudjonsson, Eduardo N. ChiniJohn Varga*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number101902
JournaliScience
Volume24
Issue number1
DOIs
StatePublished - Jan 22 2021

Funding

This work was supported in part by grants from the National Institutes of Health (NIH) and National Institute on Aging (NIA) grants 1R56AG054207 (J.V.), AR074523 (J.V. and E.N.C.), AG-26094 (E.N.C), AG58812 (E.N.C), AR070285 (B. K.), AR073371 (S.D.M. and J.V.), P30 AR073371 (J.G.), Scleroderma Foundation Research Grant (D.X.), and the Glenn Foundation for Medical Research via the Paul F. Glenn Laboratories for the Biology of Aging at the Mayo Clinic (E.N.C). We gratefully acknowledge Mary Carns and Kathleen Aren for technical assistance, as well as the Northwestern Mouse Histopathology & Phenotyping Core, Pathology Core, and Nikon Imaging Center and Small Animal Imaging Facility Core for their services. We acknowledge GSK for providing 78c and ChromaDex for providing NR. This work was supported in part by grants from the National Institutes of Health (NIH) and National Institute on Aging (NIA) grants 1R56AG054207 (J.V.), AR074523 (J.V. and E.N.C.), AG-26094 (E.N.C), AG58812 (E.N.C), AR070285 (B. K.), AR073371 (S.D.M. and J.V.), P30 AR073371 (J.G.), Scleroderma Foundation Research Grant (D.X.), and the Glenn Foundation for Medical Research via the Paul F. Glenn Laboratories for the Biology of Aging at the Mayo Clinic (E.N.C). We gratefully acknowledge Mary Carns and Kathleen Aren for technical assistance, as well as the Northwestern Mouse Histopathology & Phenotyping Core, Pathology Core, and Nikon Imaging Center and Small Animal Imaging Facility Core for their services. We acknowledge GSK for providing 78c and ChromaDex for providing NR. J.V. E.N.C. and B.S. generated the hypothesis, designed all experiments, analyzed the results, and prepared the manuscript. B.S. W.X.W. L.K. and S.B. conducted and performed in vivo and the main in vitro experiments. B.K. J.W. and J.G. analyzed gene expression in human and mouse samples. G.C.O. J.M.E.N. C.C.S.C. and E.N.C analyzed NAD metabolism. R.G.M. Q.W. D.G. and B.S. analyzed tissue morphology and expression levels and performed experiments with cultured cells. D.X. S.M. and M.A. performed flow cytometry and data analysis. P.C. determined lung fibrosis score. D.P. performed lung CT imaging and data analysis. All authors contributed to the preparation of the manuscript. J.V. reports being a consultant for TeneoBio and Mitobridge. C.C.S.C. reports holding a patent on the use of CD38 inhibitors for metabolic diseases that is licensed by Elysium Health. E.N.C reports being a consultant for TeneoBio, Calico, Mitobridge, and Cyokinetics. E.N.C is on the advisory board of Eolo pharmaceutical, Argentina. J.G.'s research was support by grants from Lilly, Almirall, AbbVie, Kyowa Kirin, and BMS/Celgene; and he reports serving on the Advisory Board of Lilly, BMS, Novartis, Kyowa Kirin, AnaptysBio, and Almirall.

Keywords

  • Human Metabolism
  • Immunology
  • Molecular Biology

ASJC Scopus subject areas

  • General

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