Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor

Abstract

Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes were blocked by inosine treatment. Additionally, inosine consistently inhibited IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; A2AR: adenosine A2A receptor; IL-17: interleukin-17; IL-4: interleukin-4.

Gut Microbiota Composition and Fecal Metabolic Phenotype in Patients With Acute Anterior Uveitis

“…54 Inosine has been shown to inhibit the production of IL-17 and -14 and to stimulate the release of adenosine A2A receptor (A2AR) in experimental autoimmune encephalomyelitis (EAE) models. 55 The role of increased linoleic acid and azelaic acid in AAU patients or inosine in HLA-B27 þ patients is unclear and deserves further study. It has been shown that short chain fatty acids (SCFAs) could promote the differentiation of Treg cells and are found to be implicated in several autoimmune diseases.…”

Serum Uric Acid Level and Multiple Sclerosis: A Mendelian Randomization Study

“…The information of effect allele, other allele, effect allele frequency, and sample size was also used to perform the MR analysis. SNPs were excluded from the MR analysis if their measured linkage disequilibrium had an r (Junqueira et al, 2017) greater than 0.01. We calculated the linkage disequilibrium using the CEU panel of the phase 3 data of the 1000 Genomes Project as the reference panel (The 1000 Genomes Project Consortium et al, 2015).…”

“…The etiology of MS is varied and not fully understood (Dobson and Giovannoni, 2019). As a potent scavenger of peroxynitrite, previous studies suggested that UA may play an important role in the development of MS (Liu et al, 2012;Junqueira et al, 2017). An updated meta-analysis using data from case-control studies showed that the serum UA level was lower in persons with MS than in healthy controls (Wang et al, 2016).…”

Inosine – a Multifunctional Treatment for Complications of Neurologic Injury

“…Under physiologic conditions, blood levels of inosine are increased by exercise and ingestion of certain foods (organ meats, beer, spinach) and exhibit diurnal variations. Over the past two decades, inosine has been shown to evoke significant improvements in motor function and visceral organ control in preclinical models of neurologic injury including SCI [19][20][21][22][23][24], stroke [25][26][27][28][29], traumatic brain injury [30], multiple sclerosis (MS) [31][32][33][34][35] and Parkinson's disease (PD) [36] through its ability to enhance the growth of axon collaterals from undamaged neurons. The basis of these beneficial effects stems from its antioxidant, anti-inflammatory, axogenic and neuroprotective properties (reviewed in [37]).…”

“…As discussed below, inosine has been shown to bind directly to A 1 , A 2A and A 3 receptor subtypes [65][66][67][68], with affinities that are typically lower than that of adenosine. Although direct binding of inosine to A 2B has not been demonstrated, there is convincing evidence to suggest that inosine interacts functionally with all 4 adenosine receptor subtypes, to elicit a variety of effects depending on species and biological context [24,35,[68][69][70][71][72]. A summary of the diverse biological activities of inosine mediated by adenosine receptors is provided in Table 1.…”