G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Abstract

Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes. Allergen-induced mast cell activation is central to the pathogenesis of asthma and other allergic diseases. Presently, most pharmacological agents for the treatment of allergic disease target receptors for inflammatory mediators. Many of these mediators, such as histamine, are released by mast cells. Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell. In vitro studies using cultured human and mouse mast cells, and studies of mice lacking A 2B receptors, suggest that adenosine receptors, specifically the G s -coupled A 2A and A 2B receptors, might provide such a target. Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo. We identify A 2B as the primary receptor limiting mast cell degranulation, whereas the combined activity of A 2A and A 2B is required for the inhibition of cytokine synthesis.

Purinergic Signaling in Mast Cell Degranulation and Asthma

“… Ryzhov et al (2008b) demonstrated that BMMCs in A 2B AR KO mice display two distinct phenotypes. One effect is enhanced antigen-induced degranulation, consistent with an inhibitory role of A 2B AR in degranulation as reported by Hua et al (2013a) . The other effect observed in A 2B AR KO mice is loss of NECA-induced increases of IL-13 leading to vascular endothelial growth factor (VEGF) secretion.…”

“…Thus, A 2B AR agonists rather than antagonists can be considered as a therapy for asthma. Hua et al (2013a) reported that the two Gs-coupled A 2A and A 2B ARs differentially limit antigen-induced mast cell activation. By comparing mast cell responses of mice with various combinations of AR KOs, they showed that AR agonists can modulate mast cell degranulation and induction of cytokine production both in vitro and in vivo .…”

“…Adenosine 5′-monophosphate (AMP) 1 also induces bronchoconstriction in asthmatic patients, and this compound, which forms adenosine in situ , is used in inhalation challenge testing ( Isogai et al, 2017 ). Additionally, adenosine, ATP, and allergens can induce mast cell degranulation independently or synergistically ( Nunomura et al, 2010 ; Hua et al, 2013a ).…”

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…A2BR activation limits cells degranulation [84]. The combination of A2AR and A2BR activation is required for the inhibition of cytokine synthesis both in vitro and in vivo [85,86]. MCs isolated from wild type (WT), not A2BR knocked out (KO) mice, release IL-13 and VEGF in response to extracellular ADO, suggesting the role of A2BR in angiogenesis [87].…”

Purinergic signalling and immune cells

“…Both A 2A and A 2B receptors were identified on mouse bone marrow-derived mast cells [ 142 ]. Using knockout mice, it was demonstrated that the inhibition of mast cell degranulation by adenosine in mediated by the A 2B receptor, while the combined action of A 2B and A 2A receptors is responsible for the inhibition of cytokine production [ 143 ]. However, the role of adenosine receptors in mast cell regulation is more complex, since the stimulatory effect of adenosine on the release of angiogenic factors such as vascular endothelial growth factor (VEGF) was shown to involve a cooperation between A 2B and A 3 receptors [ 144 , 145 ].…”