In Zusammenarbeit mit Eduardo Duarte
Multiple Sclerosis (MS) is a chronic inflammatory disease that affects the Central Nervous System (CNS) causing demyelination and neuroaxonal degeneration. Research has shown that many signaling pathways are dysfunctional in MS and contributes to its development and progression. In this regard, adenosine (ADO) is a molecule largely involved in cell communication and has a prominent role in the modulation of CNS physiology, immunity and behavior. ADO is generated by the action of CD39 and CD73, enzymes that converts ATP/ADP to AMP and subsequently to ADO, respectively. Once generated, ADO can bind to four different purinergic (P1) receptors: adenosine A1 receptor (A1R), adenosine A2A receptor (A2AR), adenosineA2B receptor (A2BR) and adenosine A3 receptor (A3R).
ADO, its receptors and enzymes that mediate ADO signaling pathway initiation and termination have complex roles in the pathogenesis of MS. For instance, A1R, which can inhibit inflammation and modulate myelination, was found to be decreased in PBMCs and microglia/macrophages of MS patients. Curiously, activation of A1R by agonists caused increased permeability in the blood-brain-barrier (BBB), which was also observed when A2AR was activated.
Moreover, A2AR seems to play a protective, anti-inflammatory role as demonstrated by genetic deletion of this receptor in mice, although its levels are high in lymphocytes from MS patients, which may suggest a compensation mechanism. Furthermore, high levels of A2BR were found in PBMCs from MS patients, which is consistent with the fact that ADO binding to this receptor is often observed during pathological conditions, such as inflammation, hypoxia and trauma. Regarding the enzymes, CD39+ regulatory T cells (Tregs) number and function were low in MS patients. CD39 and CD73 levels were shown to be high in the cerebrospinal fluid (CSF) of MS patients, but high levels were also reported in PBMCs of the same patients. These results reveal novel molecular targets that could be explored in the future in the repurposing or design of drugs to treat MS.
Duarte-Silva E, Ulrich H, Oliveira-Giacomelli Á, Hartung HP, Meuth SG, Peixoto CA. The adenosinergic signaling in the pathogenesis and treatment of multiple sclerosis. Front Immunol. 2022;13:946698. Published 2022 Jul 28. doi:10.3389/fimmu.2022.946698