The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases

Abstract

CD38 (Cluster of Differentiation 38) is a multifunctional ecto-enzyme that metabolizes NAD+ and mediates nicotinamide dinucleotide (NAD+) and extracellular nucleotide homeostasis as well as intracellular calcium. CD38 is also an emerging therapeutic target under conditions in which metabolism is altered including infection, aging, and tumorigenesis. We describe multiple enzymatic activities of CD38, which may explain the breadth of biological roles observed for this enzyme. Of greatest significance is the role of CD38 as an ecto-enzyme capable of modulating extracellular NAD+ precursor availability: 1 to bacteria unable to perform de novo synthesis of NAD+; and 2 in aged parenchyma impacted by the accumulation of immune cells during the process of 'inflammaging'. We also discuss the paradoxical role of CD38 as a modulator of intracellular NAD+, particularly in tumor immunity. Finally, we provide a summary of therapeutic approaches to CD38 inhibition and 'NAD+ boosting' for treatment of metabolic dysfunction observed during aging and in tumor immunity. The present review summarizes the role of CD38 in nicotinamide nucleotide homeostasis with special emphasis on the role of CD38 as an immunomodulator and druggable target.

Keywords: CD38; NAD+; NADase; aging; cancer; macrophages; metabolism; senescence.

Figure 1

Role of CD38 in NAD⁺ metabolism. CD38 is predominantly expressed on immune cells and metabolizes nicotinamide nucleotides (NAD⁺ and NMN) to ADPR and cADPR, which results in the mobilization of calcium. Although intracellular CD38 is present in the cytoplasm and in the membranes of organelles, a vast majority of CD38 activity is extracellular, which results in degradation of NAD⁺ precursors (e. g., NMN) necessary for NAD⁺ synthesis. Extracellular activity of CD38 has wide ranging implications for NAD⁺ homeostasis in the context of infection, metabolic dysfunction, aging, and tumor biology.

Figure 2

CD38 is primarily an NAD⁺ glycohydrolase, which degrades nicotinamide nucleotides. In addition to the NAD⁺ glycohydrolase activity, CD38 exhibits inefficient ADP-ribosyl cyclase activity and mediates a base-exchange of vitamin B3 bases in the presence of excess nicotinamide analogs.

Figure 3

CD38 may alter the availability of NAD⁺ precursors. CD38+ cells may limit the growth of pathogens such as H. aegyptius, H. influenzae, H. haemolyticus, H. parainfluenzae, and H. parahaemolyticus by degrading extracellular NAD⁺ precursors required for NAD⁺ synthesis in bacteria. In the absence of NAD and its precursors (V factor), pathogens undergo metabolic collapse.

Figure 4

NAD⁺ decline has been implicated in several diseases and age-related conditions. NAD⁺ decline has been implicated in the biology of aging and in several conditions in rodents. In humans, NAD decline has been implicated in pellagra, acute kidney injury, and the fetal malformation syndrome (VACTERL association), which affects many organ systems during development.

Figure 5

CD38 expression in macrophages mediate “inflammaging.” The senescence associated senescent phenotype (SASP) appears to drive the expression of CD38 in macrophages. During inflammaging, CD38+ macrophages accumulate in aging tissues and potentiate the decline of precursors necessary for NAD⁺ synthesis.

Figure 6

Role of CD38 in immunometabolism and tumor biology. Using a strategy that merges Th1 and Th17 cells into a hybrid Th1/Th17 cell, the CD38-NAD⁺ axis undergoes metabolic reprogramming. Reprogramming results in a shift toward glutamine-driven oxidative phosphorylation, which improves T cell survival, immune cell recruitment to the tumor, and T cell memory. Th1/Th17 hybrid cells also demonstrate reduced expression of CD38 and higher levels of NAD⁺, which serves as a substrate for NAD⁺ -dependent Sirt1 deacetylase activity that is essential to the T cell response.