Correction: The Stimulatory Adenosine Receptor ADORA2B Regulates Serotonin (5-HT) Synthesis and Release in Oxygen-Depleted EC Cells in Inflammatory Bowel Disease

Abstract

Objective:We recently demonstrated that hypoxia, a key feature of IBD, increases enterochromaffin (EC) cell 5-HT secretion, which is also physiologically regulated by the ADORA2B mechanoreceptor. Since hypoxia is associated with increased extracellular adenosine, we wanted to examine whether this nucleotide amplifies HIF-1a-mediated 5-HT secretion. Design:The effects of hypoxia were studied on IBD mucosa, isolated IBD-EC cells, isolated normal EC cells and the EC cell tumor derived cell line KRJ-1. Hypoxia (0.5% O 2 ) was compared to NECA (adenosine agonist), MRS1754 (ADORA2B receptor antagonist) and SCH442146 (ADORA2A antagonist) on HIF signaling and 5-HT secretion. Antisense approaches were used to mechanistically evaluate EC cells in vitro. PCR and western blot were used to analyze transcript and protein levels of HIF-1a signaling and neuroendocrine cell function. An animal model of colitis was evaluated to confirm hypoxia:adenosine signaling in vivo.Results: HIF-1a is upregulated in IBD mucosa and IBD-EC cells, the majority (,90%) of which express an activated phenotype in situ. Hypoxia stimulated 5-HT release maximally at 30 mins, an effect amplified by NECA and selectively inhibited by MRS1754, through phosphorylation of TPH-1 and activation of VMAT-1. Transient transfection with Renilla luciferase under hypoxia transcriptional response element (HRE) control identified that ADORA2B activated HIF-1a signaling under hypoxic conditions. Additional signaling pathways associated with hypoxia:adenosine included MAP kinase and CREB. Antisense approaches mechanistically confirmed that ADORA2B signaling was linked to these pathways and 5-HT release under hypoxic conditions. Hypoxia:adenosine activation which could be reversed by 59-ASA treatment was confirmed in a TNBS-model. Conclusion:Hypoxia induced 5-HT synthesis and secretion is amplified by ADORA2B signaling via MAPK/CREB and TPH-1 activation. Targeting ADORA2s may decrease EC cell 5-HT production and secretion in IBD.

Adenosine signalling in T‐cell activation favours development of IL‐17 positive cells with suppressive properties

“…In addition, HIF1A induces regulatory phenotypes in T-cells [91,92] and significantly induces IL-10 expression in Th17 cells [89], affecting genes in metabolic, anti-apoptotic, cell cycle and T-cell functional pathways. Interestingly, adenosine receptor engagement increases hypoxic signalling while HIF1A upregulates adenosine receptors [93][94][95][96], thereby closely linking hypoxic and adenosinergic signalling. Thus, our data suggest that hypoxic signalling may act as a link between adenosine receptor stimulation and generation of noninflammatory Th17 cells.…”

Specific adverse outcomes associated with selective serotonin reuptake inhibitors use in COVID-19 patients might be potentiated by remdesivir use

“…Adenosine may also hamper immune response mediated by T cell and reduce inflammation which might suggest rationale for predisposition to observed bacteriemia in RDV users (Galan et al, 2009; Layland et al, 2014; Lucijanic et al, 2022, 2023; Vijayan et al, 2017). It has been shown that a hypoxemic setting in inflammatory bowel disease stimulates serotonin synthesis and release and is potentiated by adenosine agonist (Dammen et al, 2013). Although a connection between SSRI and RDV pharmacodynamics remains elusive and current mechanisms unknown, our study suggests that these two drug classes might have a higher incidence of adverse events when used together.…”

The Adenosine A2B Receptor Drives Osteoclast-Mediated Bone Resorption in Hypoxic Microenvironments

“…The adenosine A 2B receptor–HIF signaling pathway is one intracellular pathway that would likely not be activated by A 2B receptor agonists administered in normoxic culture, due to the requirement for hypoxia to cause inactivation of the HIF-regulating prolyl hydroxylase (PHD) enzymes and subsequent stabilization of HIF-α proteins [7,49]. Adenosine and the A 2B receptor amplify HIF signaling under hypoxic conditions, contributing to further stabilisation of HIF protein and activation of HIF-mediated transcription in neuroendocrine enterochromaffin cells of the gut [50], smooth muscle cells [32], oral squamous cell carcinoma cells [51], cardiomyocytes [33] and microglial cells [52], as well as in adenosine deaminase-deficient mice and in vivo models of sickle cell disease [32]. Activation of this signaling pathway leads to an A 2B receptor- and HIF-dependent increase in glycolytic metabolism [33,52].…”