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Abstract Number: 119

Targeting Dysregulated CD38/NAD+ Homeostasis Mitigates Multiple Organ Fibrosis

Bo Shi1, Wenxia Wang2, Swati Bhattacharyya1, Benjamin Korman3, Roberta Goncalves Marangoni1, David Camp4, Paul Cheresh5, Guilherme de Oliveira6, Eduardo Chini7 and John Varga1, 1Northwestern University, Chicago, IL, 2Feinberg School of Medicine, Northwestern University, Chicago, IL, 3Department of Rheumatology, Northwestern University, Feinberg School of Medicine Scleroderma Program, Chicago, IL, 4Division of Pulmonary and Critical Care, Northwestern University, Chicago, IL, 5Northwestern University, CHICAGO, IL, 6Mayo Clinic of Medicine, Rochester, MN, 7Kogod Center on Aging, Mayo Clinic, Rochester, MN

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: fibrosis and systemic sclerosis

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Session Information

Date: Sunday, October 21, 2018

Session Title: Systemic Sclerosis and Related Disorders – Basic Science Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Persistent myofibroblast activation underlies unresolving multi-organ fibrosis in systemic sclerosis (SSc). We had shown that fibrosis is associated with reduced expression of NAD-dependent sirtuins (SIRTs) 1 and 3. The activity of SIRTs is determined by availability of NAD+, which in turn is regulated by CD38, the main NAD-consuming enzyme.  We had shown that during chronological aging, up-regulation of CD38 drives cellular NAD+ consumption, resulting in reduced SIRT activity, mitochondrial dysfunction, cellular metabolic collapse and senescence. We sought to test the hypothesis that biological aging is accelerated in SSc, and causes NAD+ depletion and metabolic imbalance contributing to cellular senescence and fibrosis. We also hypothesize restoring NAD+ homeostasis will prevent fibrosis in mouse model.

Methods: Expression and regulation of NAD+ metabolic pathway enzymes and fibrotic pathway genes was examined in human and mouse SSc transcriptomes, tissue biopsies, and explanted fibroblasts. Cellular senescence was investigated by immunostaining. Fibrosis and inflammation induced by chronic subcutaneous bleomycin were examined in aged mice treated with the orally available NAD+ precursor nicotinamide riboside (NR), and a novel potent and selective CD38 inhibitor (78c). <>Results: The number of p16-positive senescent cells was elevated in SSc skin biopsies. Moreover, levels of CD38 transcript and protein were increased in SSc skin biopsies as well as explanted skin fibroblasts compared to matched controls. CD38 expression was also elevated in skin from mice with fibrosis. Notably, CD38 levels showed strong correlation with the TGF-ß signature (p<0.0001, r=0.42) as well as Modified Rodnan skin score (p<0.003, r =0.34), while an anti-correlation with SIRT activity was observed. Overexpressing CD38 lowered cellular SIRT activity and augmented, while CD38 inhibition diminished, fibrotic responses in cultured fibroblasts. NR alone, or combined with the CD38 inhibitor 78c, abrogated TGF-ß-mediated fibrotic responses and Smad-dependent transcriptional activity in fibroblasts. Treatment of aged mice with 78c alone, or combined with NR supplementation, attenuated fibrosis and inflammation in the skin and lungs. These anti-fibrotic effects were correlated with increased tissue levels of NAD+.

Conclusion: Expression of CD38 and other NAD-consuming enzymes is elevated in fibrotic skin. Elevated CD38 potentially causes cellular NAD+ depletion and reduced SIRT activity with protein hyperacetylation. SIRT dysfunction in turn contributes to persistent fibroblast activation and senescence underlying unresolving fibrosis (Fig.1). Restoring NAD+ homeostasis through CD38 inhibition and NR supplementation ameliorated fibrosis in mouse models and could represent a novel strategy for the treatment of SSc.

 

 


Disclosure: B. Shi, None; W. Wang, None; S. Bhattacharyya, None; B. Korman, None; R. G. Marangoni, None; D. Camp, None; P. Cheresh, None; G. de Oliveira, None; E. Chini, None; J. Varga, BSM, 2,Pfizer, Inc., 2,Boehringer, 5,Mitsubishi, 5,Corbus, 5,Scleroderma Foundation, 6.

To cite this abstract in AMA style:

Shi B, Wang W, Bhattacharyya S, Korman B, Marangoni RG, Camp D, Cheresh P, de Oliveira G, Chini E, Varga J. Targeting Dysregulated CD38/NAD+ Homeostasis Mitigates Multiple Organ Fibrosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/targeting-dysregulated-cd38-nad-homeostasis-mitigates-multiple-organ-fibrosis/. Accessed March 23, 2023.
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