Expression and function of adenosine receptors in human dendritic cells

470

432

Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

470

432

“…In light of these findings, it is interesting to note that accumulation of dendritic cells at target sites is modulated through the adenosine receptor pathway. In studies not involving perceived stress [41], immature dendritic cells migrated to inflammatory sites along an adenosine gradient via an A 1 receptor-mediated mechanism, with subsequent down-regulation of these surface A 1 receptors upon dendritic cell maturation. Thus, the adenosine A 1 receptor pathway could potentially affect how the contact hypersensitivity reaction responds to perceived stress via modulation of either neutrophil or dendritic cell trafficking; cellular activities that are known to be affected under conditions of stress.…”

Section: Discussionmentioning

confidence: 99%

Restraint stress fails to modulate cutaneous hypersensitivity responses in mice lacking the adenosine A1 receptor

Oliver

Mathew

Wilder

et al. 2011

Psychological stress has long been associated with effects on immune function and disease. In particular, differential effects of acute and chronic stress on skin immunity occur in the rodent restraint stress model, with acute stress enhancing and chronic stress suppressing cutaneous hypersensitivity. Extracellular levels of adenosine are known to modulate diverse biological activities in the CNS and peripheral tissues and serve an important protective function against physiological stressors such as inflammation and ischemia. In this study, we utilized the restraint stress model and the skin sensitizer dinitrofluorobezene to test the hypothesis that perceived stress influences contact hypersensitivity through an adenosine A 1 receptor-mediated mechanism. We subjected hapten-sensitized A 1 receptor knockout (A1 KO) mice and their wild-type (WT) littermates to either acute (2.5 h) or chronic (5 h daily×4 weeks) restraint stress, followed by hapten re-challenge of the pinna. Daily measurements of the resulting pinna swellings from each group were compared to reactions in non-stressed controls. In WT mice, pinna swelling was augmented in acutely stressed mice and suppressed in the chronically stressed group. In contrast, contact hypersensitivity responses in the A1 KO mice failed to be affected by either acute or chronic stress. Absence of the adenosine A 1 receptor did not affect levels of plasma corticosterone or urine catecholamines under these stressful conditions but did lead to reduced numbers of circulating neutrophil granulocytes compared to stressed WT animals. These results suggest that the adenosine A 1 receptor pathway plays a role in the process by which perceived psychological stress influences the contact hypersensitivity response.

“…With such a wide distribution, A2AAR has been linked to several processes, including protection against ischemia-reperfusion injury [22], coronary vasodilatation [23], sleep regulation [24], control of inflammation [21], citing but a few biological events related to such receptor. Regarding the immune system, A2AAR signaling influences a myriad of events, including dendritic cell maturation [25]; inhibition of neutrophil phagocytosis and adhesion [26,27]; suppression of proinflammatory response of macrophages [28]; inhibition of inflammatory cytokine production by lymphocytes [29], control of CD8 Tcells cytotoxicity; and modulation of Treg function [30,31]. Recently, it has also been demonstrated that deletion of A2AAR in mice models causes a decline in the number of naive T-cells in the periphery.…”

Section: Adenosine Receptors-a Brief Overviewmentioning

confidence: 99%

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Bravo

Carvalho

Saldanha-Araújo

2016

Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. This nucleotide is produced, in part, by the action of the ectoenzymes CD39 and CD73. Interestingly, these proteins are expressed on the cell surface of regulatory T-cells (Tregs) and mesenchymal stromal cells (MSCs)-two cell populations that have emerged as potential therapeutic tools in the field of cell therapy. In fact, the production of adenosine constitutes a mechanism used by both cell types to control the immune response. Recently, great scientific progress was obtained regarding the role of adenosine in the inflammatory environment. In this context, the present review focuses on the advances related to the impact of adenosine production over the immune modulatory activity of Tregs and MSCs, and how this nucleotide controls the biological functions of these cells. Finally, we mention the main challenges and hurdles to bring such molecule to clinical settings.