CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets

Abstract

CD38 is an ectoenzyme that catalyzes the conversion of β-nicotinamide adenine dinucleotide (β-NAD) to cyclic adenosine diphosphoribose (cADPR) and adenosine diphosphoribose (ADPR) and NADP to nicotinic acid adenine dinucleotide phosphate (NAADP) and adenosine diphosphoribose-2’-phosphate (ADPR-P). The metabolites of NAD and NADP have roles in calcium signaling in different cell types including airway smooth muscle (ASM) cells. In ASM cells, inflammatory cytokines augment CD38 expression and to a greater magnitude in cells from asthmatics, indicating a greater capacity for the generation of cADPR and ADPR in ASM from asthmatics. CD38 deficient mice develop attenuated airway responsiveness to inhaled methacholine following allergen sensitization and challenge compared to wild-type mice indicating its potential role in asthma. Regulation of CD38 expression in ASM cells is achieved by mitogen activated protein kinases, specific isoforms of PI3 kinases, the transcription factors NF-κB and AP-1, and post-transcriptionally by microRNAs. This review will focus on the role of CD38 in intracellular calcium regulation in ASM, contribution to airway inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation, the transcriptional and post-transcriptional mechanisms of regulation of expression, and outline approaches to inhibit its expression and activity.

PTEN participates in airway remodeling of asthma by regulating CD38/Ca2+/CREB signaling

“…CD38/Ca 2+ signaling affects a wide range of biological processes, which include proliferation and differentiation [ 17 ]. Interestingly, CD38 has been suggested as a key regulator of asthma [ 18 ]. CD38 is ubiquitously expressed in ASM and its expression is augmented in asthma [ 19 ].…”

The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors

“…CD38 has been extensively studied for its role in hematological malignancies, including chronic lymphocytic leukemia [16,17] and multiple myeloma [17][18][19]. Research on CD38 and its involvement in chronic inflammatory diseases, such as rheumatoid arthritis [20,21] and asthma [22,23], indicates that the aberrant expression and hyperactivity of CD38 can tip immune responses towards disease pathology. The understanding of how this immune cell marker may influence the progression and immune evasion within solid tumors is a relatively new field.…”

Specific cyclic ADP-ribose phosphohydrolase obtained by mutagenic engineering of Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase

“…Given the wide variety of cell processes affected by calcium, many physiological and pathological situations can be mediated by cADPR in different systems, including animals, plants and protozoa. In mammals, it is an important player in processes such as: inflammatory and immune responses, including neutrophil chemotaxis 5 and T cell activation 6 ; smooth muscle cell contraction in arteries and bronchi, with participation in the hypoxic pulmonary vasoconstriction 7 , 8 and in the pathogenesis of inflammatory/allergic airway diseases 9 , 10 ; myometrium contractility, eventually contributing to delivery 11 , 12 ; myocyte contraction in adult cardiac tissue 13 , participating in angiotensin II- and β-adrenergic-induced cardiac hypertrophy 14 , 15 and in isoproterenol-induced arrhythmias 16 ; endocrine and exocrine pancreatic secretion 17 , 18 , although its role in insulin secretion and diabetes is controversial 19 ; cell proliferation and differentiation, regulating e.g. expansion of human mesenchymal stem cells and hemopoietic progenitors 20 , 21 , neuronal differentiation of PC12 cells 22 , and cardiomyocyte differentiation of mouse embryonic stem cells 23 ; and social behaviour in mice, including memory formation and spatial learning 24 , 25 , related to oxytocin secretion 26 , 27 and maybe to niacin deficiency 28 .…”