Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

Hu, Xia; Adebiyi, Morayo G.; Luo, Jialie; Sun, Kaiqi; Le, Thanh Thuy; Zhang, Yujin; H, Wu; Zhao, Shushan; Karmouty‐Quintana, Harry; Li, Hong; Huang, Aji; Wen, Yuan Edward; Zaika, Oleg; Mamenko, Mykola; Pochynyuk, Oleh; Kellems, Rodney E.; Eltzschig, Holger K.; Blackburn, Michael R.; Walters, Edgar T.; Huang, Dong; Hu, Hongzhen; Xia, Yang

doi:10.1016/j.celrep.2016.05.080

Cited by 68 publications

(61 citation statements)

References 63 publications

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“…11 It has been reported that increased TRPV1 responses in DRG neurons contribute to pain in SCD and ADA-deficient mice. 45 Decreasing adenosine with PEG-ADA enzyme therapy or interfering with ADORA2B activation in SCD and ADAdeficient mice resulted in reduced TRPV1 responses in DRG neurons, decreased IL-6 levels, and lowered mechanical and thermal hypersensitivity. 45 Although ADORA2B receptor expression is low in DRG neurons, 45 excess adenosine signaling via ADORA2B receptors on myeloid cells promotes the secretion of soluble interleukin-6 receptor (sIL-6R) and interleukin-6 (IL-6), which form the sIL-6R-IL-6 complex to trans-activate gp130 and induce TRPV1 response in DRG neurons that promotes pain response 45 (Figure 2).…”

Section: Elevated Extracellular Adenosine Contributes To Scd Pain Viamentioning

confidence: 99%

“…However, pharmacologic antagonism of ADORA2B receptor signaling by PSB1115 reduced pain sensitivity in ADA-deficient mice and SCD mice. 45 Taken together, the sustained increase in adenosine signaling via ADORA2B contributes to sickling and multiple complications, including priapism, chronic pain, and tissue damage.…”

Section: Elevated Extracellular Adenosine Contributes To Scd Pain Viamentioning

confidence: 99%

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Metabolomic and molecular insights into sickle cell disease and innovative therapies

2019

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Sickle cell disease (SCD) is an autosomal-recessive hemolytic disorder with high morbidity and mortality. The pathophysiology of SCD is characterized by the polymerization of deoxygenated intracellular sickle hemoglobin, which causes the sickling of erythrocytes. The recent development of metabolomics, the newest member of the "omics" family, has provided a powerful new research strategy to accurately measure functional phenotypes that are the net result of genomic, transcriptomic, and proteomic changes. Metabolomics changes respond faster to external stimuli than any other "ome" and are especially appropriate for surveilling the metabolic profile of erythrocytes. In this review, we summarize recent pioneering research that exploited cutting-edge metabolomics and state-of-the-art isotopically labeled nutrient flux analysis to monitor and trace intracellular metabolism in SCD mice and humans. Genetic, structural, biochemical, and molecular studies in mice and humans demonstrate unrecognized intracellular signaling pathways, including purinergic and sphingolipid signaling networks that promote hypoxic metabolic reprogramming by channeling glucose metabolism to glycolysis via the pentose phosphate pathway. In turn, this hypoxic metabolic reprogramming induces 2,3-bisphosphoglycerate production, deoxygenation of sickle hemoglobin, polymerization, and sickling. Additionally, we review the detrimental role of an impaired Lands' cycle, which contributes to sickling, inflammation, and disease progression. Thus, metabolomic profiling allows us to identify the pathological role of adenosine signaling and S1P-mediated erythrocyte hypoxic metabolic reprogramming and hypoxia-induced impaired Lands' cycle in SCD.These findings further reveal that the inhibition of adenosine and S1P signaling cascade and the restoration of an imbalanced Lands' cycle have potent preclinical efficacy in counteracting sickling, inflammation, and disease progression.

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Section: Elevated Extracellular Adenosine Contributes To Scd Pain Viamentioning

confidence: 99%

Section: Elevated Extracellular Adenosine Contributes To Scd Pain Viamentioning

confidence: 99%

Metabolomic and molecular insights into sickle cell disease and innovative therapies

2019

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“…This pain was prevented pharmacologically with the adenosine A 2B antagonist, PSB-1115 (1-propyl-8-p-sulfophenulxanthine). It was also prevented in mice lacking both ADO and adenosine A 2B receptors, suggesting that adenosine A 2B receptors are pronociceptive [80]. PSB-1115 treatment also decreased pain-related behaviors during the early and late phases of formalin-induced pain, suggesting peripheral and central activity of adenosine A 2B receptors in pain [81].…”

Section: The Role Of Adenosine In Painmentioning

confidence: 99%

The Role of Adenosine Signaling in Headache: A Review

2017

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Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine.

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“…Carbon monoxide, a heme degradation product, is generated by heme oxygenase 1, and its elevation plays a beneficial role in SCD (33,34). An elevation of adenosine (18,21,(35)(36)(37)(38) and heme (27,28) are detrimental in SCD. Thus, these factors may be the major contributors to Per2 induction.…”

Section: Discussionmentioning

confidence: 99%

Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality

Adebiyi¹,

Zhao²,

Ye³

et al. 2019

FASEB j.

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The circadian clock is important for cellular and organ function. However, its function in sickle cell disease (SCD), a life‐threatening hemolytic disorder, remains unknown. Here, we performed an unbiased microarray screen, which revealed significantly altered expression of circadian rhythmic genes, inflammatory response genes, and iron metabolic genes in SCD Berkeley transgenic mouse lungs compared with controls. Given the vital role of period 2 (Per2) in the core clock and the unrecognized role of Per2 in SCD, we transplanted the bone marrow (BM) of SCD mice to Per2Luciferase mice, which revealed that Per2 expression was up‐regulated in SCD mouse lung. Next, we transplanted the BM of SCD mice to period 1 (Per1)/Per2 double deficient [Per1/Per2 double knockout (dKO)] and wild‐type mice, respectively. We discovered that Per1/Per2 dKO mice transplanted with SCD BM (SCD → Per1/Per2 dKO) displayed severe irradiation sensitivity and were more susceptible to an early death. Although we observed an increase of peripheral inflammatory cells, we did not detect differences in erythrocyte sickling. However, there was further lung damage due to elevated pulmonary congestion, inflammatory cell infiltration, iron overload, and secretion of IL‐6 in lavage fluid. Overall, we demonstrate that Per1/Per2 is beneficial to counteract elevated systemic inflammation, lung tissue inflammation, and iron overload in SCD.—Adebiyi, M. G., Zhao, Z., Ye, Y., Manalo, J., Hong, Y., Lee, C. C., Xian, W., McKeon, F., Culp‐Hill, R., D' Alessandro, A., Kellems, R. E., Yoo, S.‐H., Han, L., Xia, Y. Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality. FASEB J. 33, 10528–10537 (2019). http://www.fasebj.org

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Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

Cited by 68 publications

References 63 publications

Metabolomic and molecular insights into sickle cell disease and innovative therapies

Metabolomic and molecular insights into sickle cell disease and innovative therapies

The Role of Adenosine Signaling in Headache: A Review

Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality

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