Mast cell adenosine receptors function: a focus on the a3 adenosine receptor and inflammation

Abstract

Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells (MCs), as an attractive drug candidate. Four subtypes (A1, A2a, A2b, and A3) of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R) in mediating hyper responsiveness to adenosine in MCs, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human MCs. The relevance of mouse studies to the human is discussed.

Keywords: A3 adenosine receptor; HMC-1; RBL-2H3; adenosine; mast cells.

Figure 1

Complexity of MC activation. A scheme illustrating the multiple stimuli that can activate MCs. The latter include the immunological, IgE-mediated pathway, interactions with neighboring cells, such as eosinophils, T cells, and fibroblasts, pathogens that act through TLRs, the c-kit ligand SCF, and numerous stimuli that activate G-proteins, either directly (e.g., basic secretagogues such as the synthetic c48/80) or by binding to GPCRs (e.g., adenosine, complement derived peptides, prostaglandins such as PGE₂, cytokines, and more). Depending on the stimulus type, activated MCs may either release preformed mediators, packaged in secretory granules (class I mediators) as well newly synthesized mediators, including metabolites of arachidonic acid (AA, class II mediators, such as prostaglandins and leukotrienes), cytokines, and chemokines (class III mediators), or may only release a subset of mediators. In some cases, the distinct stimuli interact synergistically resulting in an amplified response.

Figure 2

Signaling pathways elicited by the human and rodent A3 adenosine receptor in MCs. This model aims to integrate the signaling pathways reported in the literature, where marked in red are proposed, not yet proven, pathways. According to this model, the rodent A3R couples to Gi2, Gi3, and Gq, leading to the activation of PLD, PLCβ, and PI3Kγ. As a result, the cytosolic concentration of Ca²⁺ rises and protein kinase C (PKC) and the ERK MAP kinases are activated. According to this model, activation of PLCβ mediates MC degranulation or synergizes with the FcεRI-elicited signals to potentiate degranulation. PI3Kγ and ERK1/2 mediate respectively MC migration and class II and class III mediator formation. In contrast, the human A3R couples mainly to Gi3 leading to activation of ERK1/2 and gene up-regulation.