TGFβ Participation in the Remyelination Process Through Microglial Modulation and Oligodendrocyte Maturation

Central nervous system (CNS) diseases occur in the context of inflammation and demyelination. Demyelination is a pathological process in which myelin sheaths are lost from around axons, while remyelination is the restoration of myelin sheaths by oligodendrocytes. TGFβ is an anti-inflammatory cytokine that participates in the immune response, favors the oligodendroglial cell fate of adult neural precursor cells, and induces oligodendrocyte precursor cell (OPC) differentiation and maturation. To evaluate TGFβ participation in remyelination, in vivo experiments were performed in control and cuprizone (CPZ)-treated rats intracranially injected (IC) with either TGFβ or vehicle and analyzed after 7 days, or intraperitoneally injected (IP) TGFβ before toxin removal from the diet. After IC, TGFβ induced an increase in phagocytic microglia in control and demyelinated animals and in MAG+ cells in demyelinated animals. Likewise, IP TGF in CPZ-demyelinated animals showed lesser microgliosis and higher IL10 transcript levels in TGFβ-treated demyelinated animals. These anti-inflammatory effects coincided with an increase in myelin-associated glycoprotein (MAG)+ cells and MAG transcript expression. On the other hand, in vitro experiments were performed on primary microglial cultures and OPCs. In microglial cultures, TGFβ treatment reduced iNOS, IL1β, TNFα, and IL10 transcript levels and increased those of Arg1. TGFβ also reduced microglial phagocytic capacity after LPS exposure. In OPC cultures, TGFβ produced no changes in platelet derived growth factor receptor alpha (PDGFRα)+ and myelin basic protein (MBP)+ cells but promoted morphological complexity in OPCs and mature oligodendrocytes. These results suggest that TGFβ might have a positive action in remyelination by modulating microglial reactivity and promoting OPC maturation.