Journal
IMMUNOLOGIC RESEARCH
Volume 66, Issue 4, Pages 445-461Publisher
HUMANA PRESS INC
DOI: 10.1007/s12026-018-9011-x
Keywords
RGC-32; Astrocyte; Multiple sclerosis; Experimental autoimmune encephalomyelitis; Extracellular matrix
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Funding
- Veterans Administration Merit Award [I01BX001458]
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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- 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--induced ECM expression and the upregulation of the reactive astrocyte markers -smooth muscle actin (-SMA) and nestin. In cultured neonatal rat astrocytes, collagens I, IV, and V, fibronectin, -SMA, and nestin were significantly induced by TGF- 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--induced collagens I, IV, and V, fibronectin, and -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--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--induced reactive astrogliosis in EAE. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS.
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