Alternative adenosine Receptor activation: The netrin-Adora2b link

Abstract

During hypoxia or inflammation, extracellular adenosine levels are elevated. Studies using pharmacologic approaches or genetic animal models pertinent to extracellular adenosine signaling implicate this pathway in attenuating hypoxia-associated inflammation. There are four distinct adenosine receptors. Of these, it is not surprising that the Adora2b adenosine receptor functions as an endogenous feedback loop to control hypoxia-associated inflammation. First, Adora2b activation requires higher adenosine concentrations compared to other adenosine receptors, similar to those achieved during hypoxic inflammation. Second, Adora2b is transcriptionally induced during hypoxia or inflammation by hypoxia-inducible transcription factor HIF1A. Studies seeking an alternative adenosine receptor activation mechanism have linked netrin-1 with Adora2b. Netrin-1 was originally discovered as a neuronal guidance molecule but also functions as an immune-modulatory signaling molecule. Similar to Adora2b, netrin-1 is induced by HIF1A, and has been shown to enhance Adora2b signaling. Studies of acute respiratory distress syndrome (ARDS), intestinal inflammation, myocardial or hepatic ischemia and reperfusion implicate the netrin-Adora2b link in tissue protection. In this review, we will discuss the potential molecular linkage between netrin-1 and Adora2b, and explore studies demonstrating interactions between netrin-1 and Adora2b in attenuating tissue inflammation.

ADORA2B, transcriptionally suppressing by MYC, promotes ferroptosis of chondrocytes via inhibition of the PI3K/Akt pathway in mice with osteoarthritis

“…For example, ADORA2B has been found to act as a safety signal in inflammatory hypoxia, with the highest levels in hypoxic or inflammatory conditions. 26 The deletion of ADORA2B gene can prevent placental damage and fetal growth restriction caused by placental gland. 25 In transgenic rats, activation of ADORA2B can induce ischemia-induced inflammatory response.…”

“…In many inflammatory response studies, it has been proven that ADORA2B has an inflammatory inducing effect. For example, ADORA2B has been found to act as a safety signal in inflammatory hypoxia, with the highest levels in hypoxic or inflammatory conditions 26 . The deletion of ADORA2B gene can prevent placental damage and fetal growth restriction caused by placental gland 25 .…”

An inflammation-related gene landscape predicts prognosis and response to immunotherapy in virus-associated hepatocellular carcinoma

“…Farther blockade of CCL2/CCR2 signaling restrained liver tumour growth via stimulating T cell antitumor immune response ( 63 ). ADORA2B functioned as an endogenous feedback loop to dominate hypoxia-relevant inflammation, which was transcriptionally induced under hypoxia or inflammation by hypoxia-inducible transcription factor HIF1A ( 64 ). Furthermore, ADORA2B expression was negatively associated with OS of HCC patients.…”

HIF‐1α targeted deletion in myeloid cells decreases MDSC accumulation and alters microbiome in neonatal mice

“…However, in combination with the increased CD44 expression on T-cells, which is a marker for effector T-cells, our results show that beyond changes in myeloid cells, the intestinal lymphoid compartment of Hif1a loxP/loxP LysM Cre+ mice also shows increased proinflammatory readiness. Anti-inflammatory effects of HIF-1α have been described several times [73][74][75] often involving nucleotide metabolism [76,77] and the neuronal guidance molecule netrin-1 [75,78,79]. Thus, one possible mechanism by which lack of HIF-1α in myeloid cells could lead to decreased Treg numbers would be via the adenosine signaling pathway.…”