Altered CD38/Cyclic ADP-Ribose Signaling Contributes to the Asthmatic Phenotype

Abstract

CD38 is a transmembrane glycoprotein expressed in airway smooth muscle cells. The enzymatic activity of CD38 generates cyclic ADP-ribose from β-NAD. Cyclic ADP-ribose mobilizes intracellular calcium during activation of airway smooth muscle cells by G-protein-coupled receptors through activation of ryanodine receptor channels in the sarcoplasmic reticulum. Inflammatory cytokines that are implicated in asthma upregulate CD38 expression and increase the calcium responses to contractile agonists in airway smooth muscle cells. The augmented intracellular calcium responses following cytokine exposure of airway smooth muscle cells are inhibited by an antagonist of cyclic ADP-ribose. Airway smooth muscle cells from CD38 knockout mice exhibit attenuated intracellular calcium responses to agonists, and these mice have reduced airway response to inhaled methacholine. CD38 also contributes to airway hyperresponsiveness as shown in mouse models of allergen or cytokine-induced inflammatory airway disease. In airway smooth muscle cells obtained from asthmatics, the cytokine-induced CD38 expression is significantly enhanced compared to expression in cells from nonasthmatics. This differential induction of CD38 expression in asthmatic airway smooth muscle cells stems from increased activation of MAP kinases and transcription through NF-κB, and altered post-transcriptional regulation through microRNAs. We propose that increased capacity for CD38 signaling in airway smooth muscle in asthma contributes to airway hyperresponsiveness.

Figure 1

Altered signaling mechanisms contributing to asthmatic airway smooth muscle cell phenotype. Studies in our laboratory revealed some important changes in the HASM cells from asthmatic donors compared to the cells from nonasthmatic donors, suggesting a potential role for these mechanisms in the asthmatic phenotype of ASM cells. (a) Inflammatory cytokine TNF-α (10 ng/mL) induced differentially elevated CD38 expression in asthmatic HASM cells compared to the nonasthmatic HASM cells, as early as 6 hrs following addition of the cytokine (n = 3/nonasthmatic or asthmatic HASM cells, *P < 0.05, significantly different from the vehicle-treated controls; **P < 0.05, significantly different from the nonasthmatic HASM cells treated with TNF-α). (b) In HASM cells from asthmatic donors, TNF-α (10 ng/mL, 24 hrs of exposure) caused significant attenuation of miR-140-3p expression compared to the nonasthmatic HASM cells. The basal miR-140-3p expression levels were comparable between nonasthmatic and asthmatic HASM cells (n = 5/nonasthmatic group; n = 6/asthmatic group, *P < 0.05, significantly different from the nonasthmatic group). (c–e) (Left and right panels) HASM cells obtained from asthmatic donors showed elevated basal and TNF-α-induced activations of ERK and p38 MAP kinases compared to the nonasthmatic HASM cells. TNF-α-induced JNK MAP Kinase activation was attenuated in asthmatic HASM cells compared to the nonasthmatic cells (blots representative of 5 independent experiments). (a) and (c–e) are reproduced with permission from [12]. Panel (b) is Reproduced with permission from [28]. Altered signaling mechanisms contributing to asthmatic airway smooth muscle cell phenotype.