Abstract
Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3−/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.
Highlights
Mast cells (MCs) play a key role in human allergic airway inflammation
Based on the observations that i) Phosphodiesterase 3 (PDE3) deficiency or PDE3 inhibition (PDE3i) reduces allergic airway inflammation (Beute et al, 2018) and that ii) epithelial MCs are induced in a chronic house dust mite (HDM)-driven asthma model (Beute et al, 2018; Li et al, 2019), III) and that elevated cyclic adenosine monophosphate (cAMP) levels have an inhibitory effect on exocytosis (Alm, 1984) we hypothesize that PDE3 activity is important for mast cell function
This paper describe that MCs lacking PDE3, as well as LAD2 cells, human MCs (HuMCs), and human basophils being treated with PDE3i, showed restrained degranulation
Summary
Mast cells (MCs) play a key role in human allergic airway inflammation. The observation of bronchial epithelial MCs in asthmatic patients (Braunstahl et al, 2003) is an indication that the presence and location of MCs are important. Analyses in chronic asthma mouse models indicated that MCs can contribute to the establishment of chronic eosinophilic airway inflammation (Yu et al, 2011) They contribute to features of tissue remodeling that resemble those observed in asthma patients, including increased numbers of mucus-secreting goblet cells in the airway epithelium and increased deposition of interstitial collagen (Yu et al, 2011; Li et al, 2019). Based on the observations that i) PDE3 deficiency or PDE3i reduces allergic airway inflammation (Beute et al, 2018) and that ii) epithelial MCs are induced in a chronic house dust mite (HDM)-driven asthma model (Beute et al, 2018; Li et al, 2019), III) and that elevated cAMP levels have an inhibitory effect on exocytosis (Alm, 1984) we hypothesize that PDE3 activity is important for mast cell function. We observed that in cell cultures PDE3 inhibitors prevented and/or attenuated stimulation-induced degranulation of bone marrowderived mouse mast cells, human peripheral blood mononuclear cell (PBMC) basophils, LAD2 mast cell lines, and peripheral blood-derived human mast cells
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