Adenosine is generated from adenosine triphosphate, which is released by stressed and damaged cells. Adenosine levels are significantly increased in patients with bronchial asthma (BA) and mediate mast cell degranulation and bronchoconstriction. Over the last decade, increasing evidence has shown that adenosine can modulate the innate immune response during monocytes differentiation towards mature myeloid cells. These adenosine-differentiated myeloid cells, characterized by co-expression of monocytes/macrophages and dendritic cell markers such as CD14 and CD209, produce high levels of pro-inflammatory cytokines, thus contributing to the pathogenesis of BA and chronic obstructive pulmonary disease. We found that expression of ADORA2A and ADORA2B are increased in monocytes obtained from patients with BA, and are associated with the generation of CD14posCD209pos pro-inflammatory cells. A positive correlation between expression of ADORA2B and IL-6 was identified in human monocytes and may explain the increased expression of IL-6 mRNA in asthmatics. Taken together, our results suggest that monocyte-specific expression of A2 adenosine receptors plays an important role in pro-inflammatory activation of human monocytes, thus contributing to the progression of asthma.
Adenosine, endogenous purine nucleoside, is an ATP metabolite that also acts as an extracellular signaling molecule. The concentration of extracellular adenosine rises during hypoxia and cell damage leading to numerous pleiotropic effects. Although a high concentration of adenosine was found at burn injury, the effect has not been well elucidated. We have studied human peripheral blood myeloid cell, due to their expression of specific adenosine receptors and capacity to migrate to the site of burn injury. We have shown that myeloid cells after 72 hours of stimulation of adenosine receptors develop altered expression of surface antigens: preserved monocyte’s marker CD14 with already expressed dendritic cell markers (CD209, CD1a). Whereas untreated cells have already lost monocyte marker in 72 hours, and express CD1a more abundantly. Adenosine modified myeloid cells express also higher levels of mRNA of proinflammatory cytokines and chemoattractants (IL-6, IL-8, IL-1 b). Using mouse model of the burn injury we have shown, that adenosine modified bone marrow derived myeloid cells injected in the site of the injury promote migration of granulocytes, monocytes, macrophages, and fibroblasts on the 7th day after burn. Thus, stimulation of adenosine receptors alters differentiation and function of myeloid cells. In the site of burn injury adenosine modified myeloid cells augment cell migration due to paracrine factors.
Dendritic cells (DC) can initiate immune reactions contributing to myocardial damage and remodeling after acute myocardial infarction (AMI). Interstitial adenosine is elevated in ischemia. We have previously shown that A2B adenosine receptors attenuate DC generation from myeloid precursors. In this study we tested the hypothesis that A2B adenosine receptors on hematopoietic cells control DC accumulation after AMI. After lethal irradiation of wild type (WT) mice, we performed bone marrow transplantations from A2B receptor knockout (KO) and from WT mice to create A2BKO‐WT chimeras and WT‐WT control, respectively. After confirming that A2BKO‐WT had greater than 90% of the hematopoietic cells replaced by week 8, AMI was created by permanent ligation of the left anterior descending coronary artery. Flow cytometry analysis on day 7 after AMI revealed significantly greater accumulation of cardiac CD11c+MHCIIhigh DC in the hearts of A2BKO‐WT chimeric mice compared with WT‐WT animals (35.0 ± 4.7 and 18.3 ± 2.1 × 103 cell/heart, respectively, p<0.05). The number of DC in the hearts of sham‐operated A2BKO‐WT and WT‐WT mice was virtually the same (2.5 ± 1.7 and 3.2 ± 1.0 × 103 cell/heart, respectively). We conclude that activation of A2B adenosine receptors on hematopoietic cells significantly attenuates AMI‐induced accumulation of CD11c+MHCIIhigh DC in the heart. Support: R01HL095787 and R01CA138923.
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