CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets
Deepak A. Deshpande a, Alonso G.P. Guedes b, Frances E. Lund c, Subbaya Subramanian d, Timothy F. Walseth e, Mathur S. Kannan f
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.
Introduction
Asthma is a chronic inflammatory disease of the lung affecting over 300 million people globally. Despite several decades of research on asthma pathophysiology and pharmacology, efficacious anti-asthma medications continue to be an unmet medical need as more than half of asthmatics are inadequately controlled. Fulfilling this need involves, in part, identifying novel therapeutic targets for asthma. Allergen exposure in susceptible individuals leads to airway inflammation characterized by release of mediators such as cytokines and chemokines. These molecules regulate the expression of a variety of genes in the resident airway cells including airway smooth muscle (ASM) cells leading to important phenotypic changes, including airway remodeling and heightened bronchoconstriction.
Different cell types mediate the structural and functional changes underlying the asthmatic phenotype. For example, immune cells account for inflammatory response to allergen and smooth muscle cells contribute toward hyperresponsiveness and bronchoconstriction. The ASM is also capable of modulating local inflammatory response via production and release of chemokines and cytokines. Interestingly, we and others have demonstrated that CD38, a plasma membrane bound multifunctional enzyme, is expressed on immune and ASM cells, and plays roles in the orchestration of immune responses, regulation of ASM contraction and airway hyperresponsiveness. Therefore, CD38 is an attractive therapeutic target in asthma (Fig. 1). This review summarizes the data highlighting the role of CD38 in asthma pathogenesis with an emphasis on approaches to therapeutically target CD38 in asthma.
Section snippets
Receptor and enzymatic functions of mammalian CD38
The protein encoded by CD38 is a type II transmembrane glycoprotein with a molecular weight of ~ 45 kDa (Ferrero et al., 2000, Lee, 2006, Zocchi et al., 1993). CD38 expression is ubiquitous and has been described in smooth muscle cells (Deshpande et al., 2003, White et al., 2000), pancreatic cells (Okamoto, Takasawa, & Nata, 1997), astrocytes (Banerjee et al., 2008, Kou et al., 2009, Mamik et al., 2011), and in B lymphocytes (Deaglio et al., 2003, Malavasi et al., 2011, Morabito et al., 2002).
CD38/cADPR in the regulation of intracellular calcium in airway smooth muscle
Our laboratory undertook studies to delineate the contribution of the two major pathways of SR calcium release, namely that mediated by activation of the IP3-receptor channels and that mediated by activation of the ryanodine receptor channels (Deshpande et al., 2003, Kannan et al., 1997, Kotlikoff et al., 2004, Prakash et al., 1998). The involvement of CD38-derived cADPR in the regulation of intracellular calcium responses to agonists has been supported by studies in our laboratory (Fig. 2).
Calcium regulation in airway smooth muscle by inflammatory cytokines
Airflow limitation that occurs in inflammatory diseases such as asthma arises from heightened contraction of ASM. Contraction of ASM is mediated by spasmogens that act via G-protein-coupled receptors and include acetylcholine released from post-ganglionic parasympathetic nerve terminals within the airways, and histamine, leukotrienes and prostaglandins that are released from mast cells. Regulation of smooth muscle contraction is achieved by phosphorylation of myosin light chain (MLC) by the MLC
Contribution of CD38 to airway hyperresponsiveness in mouse models of allergic airway disease
Our initial studies were directed at determining whether the CD38 knockout mice have an airway phenotype that is distinct from that of the wild-type mice. The changes in resistance to airflow and dynamic compliance following inhaled methacholine challenge were significantly attenuated in the CD38 knockout mice compared to wild-type mice (Deshpande et al., 2005). We then investigated the methacholine responsiveness of CD38 knockout and wild-type mice exposed to the asthma-relevant cytokines.
Regulation of CD38 expression in human airway smooth muscle
The cd38 gene is localized on chromosome 4 in humans and chromosome 5 in the mouse (Ferrero et al., 2000). The > 80 kb length gene encoding CD38 has 8 exons and binding sites for several transcription factors. In human myeloid cells, CD38 expression is induced by retinoic acid binding to the retinoic acid response element located within the first intron (Mehta & Cheema, 1999). Response elements for transcription factors AP-1 and NF-κB in the cd38 gene have been described in erythropoietic cells).
Design and characterization of CD38 inhibitors
CD38 is an attractive drug target due to its involvement in airway inflammation and airway hyperresponsiveness and many other physiological processes (Fig. 1). Several laboratories have developed small molecule CD38 inhibitors (Becherer et al., 2015, Blacher et al., 2015, Dong et al., 2011, Escande et al., 2013, Haffner et al., 2015, Hara-Yokoyama et al., 1996, Jiang et al., 2009, Kellenberger et al., 2011, Kwong et al., 2012, Moreau et al., 2013, Sauve and Schramm, 2002, Wall et al., 1998.
Summary and future directions
CD38, a bifunctional membrane protein, is expressed on immune cells as well as on airway mesenchymal cells such as ASM cells. Experimental data thus far suggest multiple roles of the CD38-cADPR pathway in the pathogenesis of asthma including in the regulation of allergen-induced airway inflammation and airway hyperresponsiveness. Additional studies are β-Nicotinamide needed to determine if CD38-cADPR plays a role in the regulation of features of airway remodeling such as ASM hyperplasia.
Conflict of interest
The authors declare that there are no conflicts of interest.
Funding source
The work presented in this review has been supported through grants from the National Institutes of Health (AG041265 (DAD), AI119395 (MSK)).