Background and Purpose - GPR17 is a G protein-coupled receptor activated by both uracil nucleotides and cysteinyl-leukotrienes, two families of mediators involved in inflammatory responses of Central Nervous System (CNS)1. Under physiological conditions, GPR17 is expressed in Oligodendrocyte Precursor Cells (OPCs) that also express the early marker NG2, reaches its maximal peak of expression in immature oligodendrocytes and is progressively downregulated during terminal maturation. Moreover, activation of the receptor by its endogenous ligands promotes whereas antagonists or RNA interference approaches impair OPC differentiation2,3. In brain, significant up-regulation of GPR17 was found at injury sites both in a rodent model of brain ischemia and after an acutely induced demyelination2,4. The present work was aimed at characterizing the expression pattern and distribution of GPR17 in mouse spinal cord, both under physiological conditions and in Experimental Autoimmune Encephalomyelitis (EAE), a murine model of Multiple Sclerosis. Methods and Results – EAE was induced in eight-week-old female C57/BL6 mice immunized with MOG35-55/CFA and treated with pertussin toxin (PTX) at 0 and 2 days post-immunization (DPI). Disease severity was monitored daily. Animals were sacrificed at 21 DPI in order to perform immunohistochemistry (IHC) analysis and semiquantitative real-time PCR (qRT-PCR) analysis. As already described for brain, IHC analysis revealed that, also in spinal cord, GPR17 specifically decorates a subset of early OPCs both in grey and white matter. After EAE induction, both the total number of mature CC1-positive, and GPR17-positive cells was reduced, whereas the number of NG2-positive cells was increased, suggesting disease-induced recruitment and proliferation of early progenitors. Interestingly, despite the decrease in the number of GPR17-positive cells, qRT-PCR analysis showed an up-regulation of GPR17 in the spinal cord of the same group of mice, and this seems to be related to their clinical score and to the relative increased levels of IL-1β, used as an inflammatory marker. Conclusions - Based on our data, we hypothesize that GPR17 is up-regulated in the disease to counteract demyelination, but this response is dysregulated at a post-transcription level, likely due to the inflammatory environment, resulting in impaired repair and eventually contributing to the disease. Characterization of the molecular defects of GPR17 in EAE will help re-establishing its correct function in remyelination and foster the identification of new pharmacological strategies to enhance the reparative potential of OPCs in the adult brain.
Expression pattern and distribution of the oligodendroglial receptor GPR17 in Experimental Autoimmune Encephalomyelitis, a mouse model of Multiple Sclerosis / G. Coppolino, D. Lecca, G. Menichetti, M. Fumagalli, M. Abbracchio. ((Intervento presentato al 4. convegno Next Step4 - La giovane ricerca avanza tenutosi a Milano nel 2013.
|Titolo:||Expression pattern and distribution of the oligodendroglial receptor GPR17 in Experimental Autoimmune Encephalomyelitis, a mouse model of Multiple Sclerosis|
COPPOLINO, GIUSY TINDARA (Primo)
LECCA, DAVIDE (Secondo)
ABBRACCHIO, MARIA PIA (Ultimo)
|Data di pubblicazione:||2013|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||Expression pattern and distribution of the oligodendroglial receptor GPR17 in Experimental Autoimmune Encephalomyelitis, a mouse model of Multiple Sclerosis / G. Coppolino, D. Lecca, G. Menichetti, M. Fumagalli, M. Abbracchio. ((Intervento presentato al 4. convegno Next Step4 - La giovane ricerca avanza tenutosi a Milano nel 2013.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|