Enhancement of Mast Cell Degranulation Mediated by Purinergic Receptors’ Activation and PI3K Type δ

Abstract

The potential role of purine nucleotides in the function of human lung mast cells under physiological and pathophysiological conditions was originally conceived by A.P. and E.S.S. H.N. conducted all experiments and was assisted by F.N. H.N. and A.

Degranulation of human mast cells: modulation by P2 receptors’ agonists

“…The LAD2 human-derived MC line was developed at the NIH from a patient with systemic mastocytosis ( 5 , 6 , 10 ). As recently reported, LAD2 cells express five P2YRs (P2Y1, P2Y6, P2Y11, P2Y12, and P2Y14) along with three P1Rs (A2aR, A2bR, and A3R), and two P2XRs (P2X1 and P2X7) ( 59 ). LAD2 cells express CD39 but not CD73, suggesting extracellular nucleotides could be degraded to AMP but not to adenosine ( 59 ).…”

“…ATP is unimodal, only enhancing degranulation, whereas adenosine is bimodal; at high concentrations, it inhibits degranulation and at low concentrations, it potentiates degranulation. At equimolar concentrations, ATP is more potent than adenosine in enhancing HMC degranulation ( 57 – 59 ). ATP’s enhancing effects on IgE-mediated degranulation in freshly isolated HLMC, without exposure to varied cytokine mixtures over days to weeks in cultures, is substantial and reproducible.…”

“…The text below focuses on the progress made in recent years in our understanding of the critical interaction of the extracellular purine nucleotide adenosine 5′-triphosphate (ATP), with IgE-mediated activation of the HLMC ( 57 , 58 ) and intracellular signal transduction pathway associated with IgE receptor activation in LAD2 cell line ( 6 , 59 , 60 ). Our own interest in this regard mostly relates to allergic asthma, but other important aspects of ATP’s role in pulmonary pathophysiology have been investigated including cystic fibrosis, pulmonary embolism, cough, bronchoconstriction, pulmonary fibrosis, lung cancer, mechanical ventilation-induced lung injury, and pulmonary hypertension ( 61 – 68 ).…”

“…In further experiments, a shRNA directed against PI3K(δ) and a PI3K(δ) inhibitor, compound 15e ( 150 , 151 ), suppressed ATPγS’s effect on WAS-induced degranulation enhancement, the latter in a concentration-dependent manner. In additional experiments, an antagonist of the P2Y11R and NF157 significantly inhibited the enhancing effects of ATPγS (100 μM) on WAS-induced degranulation and experiments using siRNA knockdown of the P2Y11R, which itself abolished the enhancing effects ( 59 ).…”

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

“…Extracellular ATP activated ionotropic P2X4 receptors and enhanced antigen-triggered degranulation potentiating a high affinity IgE receptor (FceRI)mediated tyrosine kinase signaling cascade. Among multiple P2Y receptor subtypes, the P2Y 11 receptor was involved in degranulation enhancement via the PI3K/protein kinase B pathway (204). Studies in rhesus macaques, that presented authentic mild to moderate forms of COVID-19 (205), have shown that SARS-CoV-2 triggered mast cell degranulation induced acute alveolar epithelial inflammation and lung injury and that prophylactic administration of MC stabilizers that blocked degranulation could dampen the SARS-CoV-2 response and prevent lung injury (206).…”