Back to Search
Start Over
Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis
- Source :
- iScience, Vol 24, Iss 1, Pp 101902-(2021), iScience
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- Summary 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.<br />Graphical Abstract<br />Highlights • CD38 shows elevated expression in skin biopsies of patients with systemic sclerosis • Elevated CD38 is associated with reduced NAD+ and augmented fibrotic responses • Genetic loss of CD38 is associated with increased NAD+ levels and attenuated fibrosis • NAD+ boosting via CD38 inhibition or NR supplementation prevents multi-organ fibrosis<br />Human Metabolism; Molecular Biology; Immunology
- Subjects :
- Immunology
Inflammation
CD38
Nicotinamide adenine dinucleotide
Human Metabolism
Article
chemistry.chemical_compound
Downregulation and upregulation
Fibrosis
immune system diseases
hemic and lymphatic diseases
medicine
lcsh:Science
Peritoneal Fibrosis
Molecular Biology
Multidisciplinary
integumentary system
biology
Chemistry
hemic and immune systems
medicine.disease
Cell biology
Sirtuin
biology.protein
lcsh:Q
NAD+ kinase
medicine.symptom
Homeostasis
Subjects
Details
- Language :
- English
- ISSN :
- 25890042
- Volume :
- 24
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- iScience
- Accession number :
- edsair.doi.dedup.....8d1f359f094cdbc3ccb08eece57ef04f