TY - JOUR
T1 - Alternative adenosine Receptor activation
T2 - The netrin-Adora2b link
AU - Yuan, Xiaoyi
AU - Mills, Tingting
AU - Doursout, Marie Francoise
AU - Evans, Scott E.
AU - Vidal Melo, Marcos F.
AU - Eltzschig, Holger K.
N1 - Funding Information:
National Institute of Health Grants R01HL154720, R01DK122796, R01HL133900 and Department of Defense Grant W81XWH2110032 to HKE; National Institute of Health Grants R01HL155950, Parker B. Francis Fellowship, and American Lung Association Catalyst Award CA-622265 to XY. National Institute of Health Grants R01 HL121228-08 to MFVM, and National Institute of Health Grants R01AR073284 to TM. National Institute of Health Grants R35HL144805 to SEE.
Publisher Copyright:
Copyright © 2022 Yuan, Mills, Doursout, Evans, Vidal Melo and Eltzschig.
PY - 2022/7/15
Y1 - 2022/7/15
N2 - 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.
AB - 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.
KW - adenosine
KW - Adora2b
KW - hypoxia
KW - inflammation
KW - netrin-1
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U2 - 10.3389/fphar.2022.944994
DO - 10.3389/fphar.2022.944994
M3 - Review article
C2 - 35910389
AN - SCOPUS:85135112064
SN - 1663-9812
VL - 13
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 944994
ER -