Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. SIRT1 is a member of the histone deacetylase class III family of proteins and is an NAD(+)-dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and plays an important role as a key regulator of a wide variety of cellular and physiological processes including DNA damage, cell survival, metabolism, aging, and neurodegeneration. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease. SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders.
Extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and can modify immune reactions. Response gene to complement (RGC)-32 plays an important role in the mediation of TGF-β downstream effects, but its role in gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis, we investigated its involvement in TGF-β-induced ECM expression and the upregulation of the reactive astrocyte markers α-smooth muscle actin (α-SMA) and nestin. In cultured neonatal rat astrocytes, collagens I, IV, and V, fibronectin, α-SMA, and nestin were significantly induced by TGF-β stimulation, and RGC-32 silencing resulted in a significant reduction in their expression. Using astrocytes isolated from RGC-32 knock-out (KO) mice, we found that the expression of TGF-β-induced collagens I, IV, and V, fibronectin, and α-SMA was significantly reduced in RGC-32 KO mice when compared with wild-type (WT) mice. SIS3 inhibition of Smad3 phosphorylation was also associated with a significant reduction in RGC-32 nuclear translocation and TGF-β-induced collagen I expression. In addition, during experimental autoimmune encephalomyelitis (EAE), RGC-32 KO mouse astrocytes displayed an elongated, bipolar phenotype, resembling immature astrocytes and glial progenitors whereas those from WT mice had a reactive, hypertrophied phenotype. Taken together, our data demonstrate that RGC-32 plays an important role in mediating TGF-β-induced reactive astrogliosis in EAE. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS.
Excessive extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and modify immune reactions. In this study we investigated first the expression of collagen types I-V, decorin and RGC-32 in MS lesions. Collagens I, III, IV and V and decorin were expressed in the perivascular space and parenchyma, and collagens I, IV and V were expressed by astrocytes that also expressed RGC-32. Since RGC-32 is involved in mediating some of TGF-β effects we investigated its role in TGF-β-induced ECM expression. In cultured astrocytes, both fibronectin and collagens I, IV and V were significantly induced after 18 h of stimulation with TGF-β. Silencing RGC-32 expression by transfecting astrocytes with siRGC-32 caused a significant reduction in the TGF-β-induced expression of collagen I (p<0.01), collagen IV (p<0.02), collagen V (p<0.05) and fibronectin (p<0.05) when compared to treatment with control siRNA. We also found that α-smooth muscle actin (α-SMA) was significantly reduced after RGC-32 silencing (p<0.05). The effect on α-SMA suggests that RGC-32 is also required for the transition of astrocytes to a reactive state. These data indicate that RGC-32 plays an important role in TGF-β-mediated induction of ECM expression in astrocytes. RGC-32 may therefore represent a useful new target for therapeutic intervention in MS.
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