Adenosine influences myeloid cells to inhibit aeroallergen sensitization.

Agonists of adenosine A2A receptors (A2ARs) suppress the activation of most immune cells and reduce acute inflammatory responses. Asthma is characterized by sensitization in response to initial allergen exposure and by airway hyperreactivity in response to allergen rechallenge. We sought to determine if A2AR activation with CGS-21680 (CGS) is more effective when CGS is administered during sensitization or rechallenge. C57BL/6 wild-type mice and Adora2a(f/f)LysMCre(+/-) mice, which lack A2ARs on myeloid cells, were sensitized with intranasal ovalbumin (OVA) and LPS. Airway sensitization was characterized by a rapid increase in numbers of IL-6(+) and IL-12(+) macrophages and dendritic cells in lungs. A2AR activation with CGS (0.1 μg·kg(-1)·min(-1) sc) only during sensitization reduced numbers of IL-6(+) and IL-12(+) myeloid cells in the lungs and reversed the effects of OVA rechallenge to increase airway hyperresponsiveness to methacholine. CGS treatment during sensitization also reduced the expansion of lung T helper (Th1 and Th17) cells and increased expansion of regulatory T cells in response to OVA rechallenge. Most of the effects of CGS administered during sensitization were eliminated by myeloid-selective A2AR deletion. Administration of CGS only during OVA rechallenge failed to reduce airway hyperresponsiveness. We conclude that myeloid cells are key targets of adenosine during sensitization and indirectly modify T cell polarization. The results suggest that a clinically useful strategy might be to use A2AR agonists to inhibit sensitization to new aeroallergens. We speculate that adenosine production by macrophages engulfing bacteria contributes to the curious suppression of sensitization in response to early-life infections.