Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension

Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B f/f -LysM Cre ) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO 2 , bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B f/f -LysM Cre mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.-Karmouty-Quintana, H., Philip, K., Acero, L. F., Chen, N.-Y., Weng, T., Molina, J. G., Luo, F., Davies, J., Le, N.-B., Bunge, I., Volcik, K. A., Le, T.-T. T., Johnston, R. A., Xia, Y., Eltzschig, H. K., Blackburn, M. R. Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension. FASEB J. 29, 50-60 (2015). www.fasebj.org

Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A 2B Receptor Antagonism

“…suggests that A 2B R may exist as a multiprotein complex in intestinal epithelia [39], which may result in varying downstream effects depending on interactions with various stimuli. Inflammation typically entails activation of immune cells and induction of cytokines, which has been reflected in the role of A 2B R in myeloid cells [22, 40]. Pulmonary A 2B Rs appear to modulate a localized inflammatory response involving enhanced secretion of chemokines and cytokines, which is consistent with our results in the lung IRI model in which A 2B R antagonism attenuated the induction of pro-inflammatory cytokines after IR.…”

Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α

“…46,47 In addition, accumulating evidence shows that macrophages, T cells, and progenitor cells are recruited in the lesions contributing to vascular remodeling. 47–49 It has also been shown that HIF- stimulated extracellular adenosine production and signaling affect the pathogenesis of PH through modulation of macrophage functional polarization 50 . Given the observation of induced CXCL12 expression in PHD2-deficient ECs, PHD2 deficiency in ECs may also promote bone marrow cell recruitment to the lung and thereby induces complex vascular remodeling.…”

Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D

“…If true, this would be an extremely important concept because this novel idea would suggest that administration of A 1 receptor antagonists would be protective in patients with a high A 1 to A 2B ratio, whereas an A 2B receptor agonist would be preferred in patients with a high A 2B to A 1 ratio (i.e., personalized medicine). However, a caveat is that A 2B receptors when activated chronically can induce pro-fibrotic and pro-inflammatory effects 62, 63 . Therefore, it may be important to limit the duration of treatment with A 2B receptor agonists to just the critical time period in which HCASMC proliferation occurs in response to injury.…”

“…Given that A 1 receptors have much higher affinity for adenosine, why would their effect not predominate? There are reports that A 1 receptors form heterodimers with A 2A receptors and β-adrenoceptors, and that heterodimer formation blocks A 1 receptor signaling 62, 63 . Therefore, one possibility is that in HCASMCs A 2B receptors directly block A 1 receptor signaling via heterodimerization.…”