Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis
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 NAD...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220310993 |
| _version_ | 1818822034652659712 |
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| author | 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. Chini John Varga |
| author_facet | 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. Chini John Varga |
| author_sort | Bo Shi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T23:17:40Z |
| format | Article |
| id | doaj.art-0de8a21c584b46638ebb6231ab5a5a27 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-18T23:17:40Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-0de8a21c584b46638ebb6231ab5a5a272022-12-21T20:48:07ZengElsevieriScience2589-00422021-01-01241101902Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosisBo Shi0Wenxia Wang1Benjamin Korman2Li Kai3Qianqian Wang4Jun Wei5Swarna Bale6Roberta Goncalves Marangoni7Swati Bhattacharyya8Stephen Miller9Dan Xu10Mahzad Akbarpour11Paul Cheresh12Daniele Proccissi13Demirkan Gursel14Jair Machado Espindola-Netto15Claudia C.S. Chini16Guilherme C. de Oliveira17Johann E. Gudjonsson18Eduardo N. Chini19John Varga20Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAPathology Core Facility, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USADepartment of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USADepartment of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USADepartment of Dermatology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester 55905 MN, USANorthwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220310993Human MetabolismMolecular BiologyImmunology |
| spellingShingle | 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. Chini John Varga Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis iScience Human Metabolism Molecular Biology Immunology |
| title | Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis |
| title_full | Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis |
| title_fullStr | Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis |
| title_full_unstemmed | Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis |
| title_short | Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis |
| title_sort | targeting cd38 dependent nad metabolism to mitigate multiple organ fibrosis |
| topic | Human Metabolism Molecular Biology Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220310993 |
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