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A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis
- Source :
- The Journal of Neuroscience. 24:1521-1529
- Publication Year :
- 2004
- Publisher :
- Society for Neuroscience, 2004.
-
Abstract
- The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR-/-) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR+/+) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR-/-animals. In addition, spinal cords from A1AR-/-mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR+/+animals. Macrophages from A1AR-/-animals exhibited increased expression of the proinflammatory genes, interleukin-1β, and matrix metalloproteinase-12 on immune activation when matched with A1AR+/+control cells. A1AR-/-macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR+/+mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis (MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases.
- Subjects :
- medicine.medical_specialty
Adenosine
Encephalomyelitis, Autoimmune, Experimental
Multiple Sclerosis
Encephalomyelitis
Biology
Severity of Illness Index
Proinflammatory cytokine
Mice
Recurrence
Caffeine
Matrix Metalloproteinase 12
Neurobiology of Disease
Internal medicine
medicine
Animals
Humans
RNA, Messenger
Receptor
Myelin Sheath
Neuroinflammation
Inflammation
Mice, Knockout
Microglia
Receptor, Adenosine A1
Macrophages
General Neuroscience
Metalloendopeptidases
medicine.disease
Adenosine receptor
Oligodendrocyte
Adenosine A1 Receptor Agonists
Up-Regulation
Disease Models, Animal
Phenotype
medicine.anatomical_structure
Endocrinology
Spinal Cord
Immunology
Disease Progression
Female
Inflammation Mediators
Interleukin-1
medicine.drug
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....20545cf9ea408589982eb486951b690f