A2B Adenosine Receptor Expression by Myeloid Cells Is Proinflammatory in Murine Allergic-Airway Inflammation

Abstract

Asthma is a chronic condition with high morbidity and healthcare costs, and cockroach allergens are an established cause of urban pediatric asthma. A better understanding of cell types involved in promoting lung inflammation could provide new targets for the treatment of chronic pulmonary disease. Due to its role in regulating myeloid cell dependent inflammatory processes, we examined A2B R expression by myeloid cells in a cockroach allergen (CRA) model of murine asthma-like pulmonary inflammation. Both systemic and myeloid tissue-specific A2B R deletion significantly decreased pulmonary inflammatory cell recruitment, airway mucin production, and pro-inflammatory cytokine secretion after final allergen challenge in sensitized mice. A2B R deficiency resulted in a dramatic reduction on Th2 type airways responses with decreased pulmonary eosinophilia without augmenting neutrophilia, and decreased lung IL-4, IL-5, and IL-13 production. Chemokine analysis demonstrated that eotaxin 1 and 2 secretion in response to repeated allergen challenge is myeloid cell A2B R dependent. In contrast, there were no differences in the levels of the CXC chemokines KC and MIP-2 in the myeloid cell A2B R deficient mice strengthening A2B R involvement in the development of Th2 type airways inflammation. Pro-inflammatory TNF-α, IFN-γ and IL-17 secretion were also reduced in systemic and myeloid tissue-specific A2B R deletion mouse lines. Our results demonstrate Th2 type predominance for A2B R expression by myeloid cells as a mechanism of developing asthma-like pulmonary inflammation.

Anti-Inflammatory or Proinflammatory Effect of an Adenosine Receptor Agonist on the Th17 Autoimmune Response Is Inflammatory Environment–Dependent

“…In general, activation of A2ARs has anti-inflammatory effects (15; 16; 35; 36), whereas activation of A2BRs promoted inflammatory responses (11; 18; 37). However, this does not apply to all immune responses.…”

“…However, this does not apply to all immune responses. For example, proinflammatory effects have been seen as a result of A2AR activation (11; 18) and anti-inflammatory effects of A2BR activation have been reported (11; 38–40). A study in A2AR −/− mice showed that they developed more severe EAE than syngeneic B6 mice, but treatment of wild-type B6 mice with an A2AR antagonist inhibited, rather than enhanced, the development of EAE (21), suggesting that the mechanisms by which adenosine agonists/antagonists affect an immune response is more sophisticated than currently thought.…”

IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response

“…It has also been shown that smooth muscle cells can signal through the A2bR to induce the downregulation of IFNγ-induced major histocompatibility class II expression (27). A2bR signaling appears to promote anti-inflammatory macrophages, however other studies have associated A2bR with inflammatory roles in disease models such as asthma, thus demonstrating diverse and perhaps tissue-specific roles for A2bR in the regulation of inflammation (28). …”

Expression of adenosine receptors in monocytes from patients with bronchial asthma

“…The important role of adenosine and adenosine receptors in activation of monocytes and monocyte-derived mature myeloid cells (macrophages and inflammatory DCs) has been demonstrated in many studies using animal models of lung inflammation [15,16,30,31]. Growing evidence indicates that levels of adenosine receptors expression are changed in the lungs of patients with BA and chronic obstructive pulmonary disease [32,33].…”

“…We demonstrated a pro-inflammatory role of A 2B during chronic pulmonary inflammation using a mouse model of allergen-induced chronic pulmonary inflammation [15]. The role of A 2B signaling in pro-inflammatory activation of monocytes has been further demonstrated in an allergic-airway inflammation with myeloid cell specific deletion of Adora2b in mouse models [16]. However, little is known about the expression of ADORA in monocytes and their functional properties in patients with BA.…”