Mouse Cd38 Stable Cell Line - CHO-K1

Functional pleiotropic exoenzyme CD38 is a glycosyl hydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD+ to ADP-ribose and nicotinamide, CD38 controls NAD+ homeostasis and the activity of NAD+-dependent cellular enzymes. CD38 has emerged as a major driver of age-related NAD+ decline, which leads to adverse metabolic states, frailty, and reduced healthspan. CD38 is upregulated in systemic sclerosis (SSc), a chronic disease characterized by multi-organ fibrosis. Here, researchers sought to test the hypothesis that inhibition of CD38 exoenzyme activity using the heavy chain monoclonal antibody Ab68 would prevent fibrosis in a mouse model of SSc characterized by NAD+ depletion by enhancing systemic NAD+. Treatment of mice with a non-cytotoxic heavy chain antibody that selectively inhibits the CD38 exoenzyme promoted NAD+ levels, which was associated with significant prevention of multi-organ fibrosis. These findings suggest that targeted inhibition of CD38 extracellular enzyme activity may be a potential pharmacological approach for treating fibrosis in systemic sclerosis (SSc).

Here, the researchers found that treatment of mice with Ab68 resulted in decreased CD38 activity and increased muscle NAD+ levels, whereas treatment with the control Ab69 did not (Figure 1A, B). Both tissue CD38 activity and NAD+ levels were significantly correlated with dermal thickness, while CD38 activity in muscle was significantly negatively correlated with NAD+ levels (Figure 1C). In addition, NMN levels in muscle were significantly increased in mice treated with Ab68, indicating a potent systemic inhibitory effect on CD38-mediated NAD+ precursor catabolism. In addition, NMN levels in muscle were negatively correlated with dermal thickness (Figure 1D). Since the deacetylase activity of sirtuins is strictly dependent on NAD+, the effect of CD38 inhibition on sirtuin function was investigated. The researchers observed that the deacetylase activities of SIRT1 and SIRT3 were significantly increased in the liver and spleen of mice treated with Ab68, while there was no significant increase in the deacetylase activities of SIRT1 and SIRT3 in the liver and spleen of mice treated with the non-inhibitory anti-CD38 antibody Ab69 (Figure 1E). In vitro treatment of CD38-overexpressing CHO cells (CHO-mCD38) with Ab68, but not Ab69, significantly increased both cellular NAD+ levels and Sirt1 and Sirt3 deacetylase activity (Figure 1F). These results suggest that by inhibiting CD38 exoenzymes, Ab68 can increase the body's NAD+ levels and promote Sirtuin activity, which provides a potential mechanistic explanation for the anti-fibrotic effect of Ab68 in mice.

Figure 1. Ab68 treatment raised levels of NAD+ and NMN and augmented Sirt1 and Sirt3 activity. (Shi B, et al., 2023)