F Montarolo1,2,3, S Perga1,2,3, S Martire1,2, F Brescia1,2, M Caldano1,2, M Lo Re2, G Panzica1,3, A Bertolotto1,2. 1. Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Turin, Italy. 2. Neurobiology Unit, Neurology - CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Turin, Italy. 3. Department of Neuroscience 'Rita Levi Montalcini', University of Turin, Turin, Italy.
Abstract
BACKGROUND AND PURPOSE: Fingolimod is a drug approved for treatment of relapsing-remitting multiple sclerosis (RRMS) that exerts its effects via sequestering lymphocytes within the lymph nodes. The drug, acting on the sphingosine-1-phosphate pathway, is involved in a plethora of processes and, to date, its mechanism of action is not completely understood. Recently, it has been demonstrated that Fingolimod increases the expression of transcription factor NR4A2 in murine brain. NR4A2 belongs to nuclear receptor family 4, group A (NR4A) along with NR4A1 and NR4A3. The role of NR4A2 in the pathogenesis of multiple sclerosis is already known and supported by its down-regulation observed in blood obtained from patients with RRMS compared with healthy controls (HCs). It is notable that NR4A2 impairment is reversed in patients with RRMS during pregnancy, which represents a transitory state of immune tolerance, associated with reduced disease activity. An inverse correlation between NR4A2 gene expression levels and clinical parameters indicates that more aggressive forms of the disease are characterized by lower levels of NR4A2. METHODS: Gene expression levels of NR4A in blood obtained from HCs, treatment-naive (T0) and Fingolimod-treated patients with RRMS were evaluated to determine their contribution to drug response. RESULTS: Gene expression levels of NR4A were down-regulated in T0 patients compared with HCs. Patients treated with Fingolimod for >2 years were characterized by higher levels of NR4A2 compared with the T0 group, approaching those of HCs. NR4A1 and NR4A3 levels were not altered. CONCLUSIONS: Involvement of the NR4A family in the pathogenesis of multiple sclerosis and a role of Fingolimod in the recovery from NR4A2 deficit can be hypothesized based on our data.
BACKGROUND AND PURPOSE:Fingolimod is a drug approved for treatment of relapsing-remitting multiple sclerosis (RRMS) that exerts its effects via sequestering lymphocytes within the lymph nodes. The drug, acting on the sphingosine-1-phosphate pathway, is involved in a plethora of processes and, to date, its mechanism of action is not completely understood. Recently, it has been demonstrated that Fingolimod increases the expression of transcription factor NR4A2 in murine brain. NR4A2 belongs to nuclear receptor family 4, group A (NR4A) along with NR4A1 and NR4A3. The role of NR4A2 in the pathogenesis of multiple sclerosis is already known and supported by its down-regulation observed in blood obtained from patients with RRMS compared with healthy controls (HCs). It is notable that NR4A2 impairment is reversed in patients with RRMS during pregnancy, which represents a transitory state of immune tolerance, associated with reduced disease activity. An inverse correlation between NR4A2 gene expression levels and clinical parameters indicates that more aggressive forms of the disease are characterized by lower levels of NR4A2. METHODS: Gene expression levels of NR4A in blood obtained from HCs, treatment-naive (T0) and Fingolimod-treated patients with RRMS were evaluated to determine their contribution to drug response. RESULTS: Gene expression levels of NR4A were down-regulated in T0 patients compared with HCs. Patients treated with Fingolimod for >2 years were characterized by higher levels of NR4A2 compared with the T0 group, approaching those of HCs. NR4A1 and NR4A3 levels were not altered. CONCLUSIONS: Involvement of the NR4A family in the pathogenesis of multiple sclerosis and a role of Fingolimod in the recovery from NR4A2 deficit can be hypothesized based on our data.