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Review
. 2017 Apr:172:116-126.
doi: 10.1016/j.pharmthera.2016.12.002. Epub 2016 Dec 7.

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

Deepak A Deshpande  1 , Alonso G P Guedes  2 , Frances E Lund  3 , Subbaya Subramanian  4 , Timothy F Walseth  5 , Mathur S Kannan  6
Affiliations
Review

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

Deepak A Deshpande et al. Pharmacol Ther. 2017 Apr.

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.

Keywords: Airway smooth muscle; Asthma; CD38; Calcium regulation; MicroRNAs.

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Conflict of interest statement

Conflict of Interest:

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. CD38-cADPR in asthma pathogenesis
Allergen-induced inflammation, remodeling, and hyperresponsiveness are the major components of asthma. Resident airway cells such as ASM cells and migrated immune cells contribute to asthma pathogenesis. CD38 is expressed on immune cells and smooth muscle cells. CD38 on immune cells functions as cell surface marker and contributes to inflammatory response in asthma. ASM is the principal contractile component of the airways and CD38 via production of cADPR, a calcium elevating second messenger, contributes to smooth muscle contractility and airway hyperresponsiveness. Regulating CD38 expression or its enzyme activity or cADPR effect in effector cells may effectively mitigate multiple features of asthma.
Figure 2
Figure 2. Model depicting CD38/cADPR-mediated calcium release and functional effect in ASM
Stimulation of ASM cells with Gq-coupled GPCR agonists results in the production of inositol 1,4,5 triphosphate (IP3) which in turn binds to its receptors on sarcoplasmic reticulum (SR). cADPR produced by the catalytic action of ADP-ribosyl cyclase (part of membrane bound protein CD38) acts as a calcium releasing second messenger presumably via ryanodine receptors (RyR) on the SR membrane. Extracellularly produced cADPR is believed to enter cell via membrane channel formed by connexin-43. Accessory proteins such as FKBP12.6 and calmodulin (CaM) are known to be involved in the cADPR-mediated calcium release. Recent studies have shown that cADPR sensitizes store-operated calcium entry via TRP channels on the plasma membrane to open and ADPR actually gates the channels. cADPR-mediated calcium release is involved in the regulation of global as well as local/compartmentalized (e.g. oscillations) calcium homeostasis in ASM cells. In vivo studies using CD38 null mice have confirmed the functional role of CD38/cADPR-mediated calcium release in the regulation of bronchomotor tone. Calcium sensitization via RhoA/ROCK contributes to ASM contraction. However, the role of cADPR in mediating calcium sensitization mechanism is not established (dotted lines). CD38 converts NADP into NAADP which is known to release calcium from intracellular stores such as lysosomes (shown on the right side of the figure).
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