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Front. Immunol. | doi: 10.3389/fimmu.2019.01187

The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, aging and metabolic diseases

 Kelly A. Hogan1, 2, Claudia C. Chini1, 2 and  Eduardo N. Chini1, 2*
  • 1Mayo Clinic College of Medicine & Science, United States
  • 2Other, United States

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, NADase, NAD+, Aging, Metabolism, Macrophages, senescence, Immune metabolism, Antibodies, Cancer, small molecule inhibitors

Received: 01 Apr 2019; Accepted: 10 May 2019.

Edited by:

Silvia Deaglio, University of Turin, Italy

Reviewed by:

Yasser M. El-Sherbiny, Nottingham Trent University, United Kingdom
Antje Garten, Leipzig University, Germany  

Copyright: © 2019 Hogan, Chini and Chini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Eduardo N. Chini, Mayo Clinic College of Medicine & Science, Rochester, 55905-0001, Minnesota, United States,