TIMP-1, induced by oncostatin M, limits inflammation and induces repair in the damaged CNS

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS), in which destruction of myelin sheaths leads to disturbed neuronal signaling. Available MS therapies modulate the immune response, but at best delay transition to the progressive phase. There is an urgent need for therapies that can reverse the permanent neurological damage. TIMP-1, identified by us as a downstream mediator of oncostatin M (OSM, produced upon CNS injury), is a possible candidate to induce CNS repair. We already revealed that CNS-targeted OSM expression in mouse models of MS re-establishes remyelination. TIMP-1, produced by astrocytes, is strongly upregulated in these mouse models after OSM treatment and has been linked to MS pathology. We hypothesize that astrocytic TIMP-1, induced by OSM, is a crucial regulator of repair in the damaged CNS by first line protection at the level of the BBB and by promoting remyelination and neuroregeneration. While the main focus goes to MMP-independent TIMP-1 functions, anti-proteolytic activity is also taken along. We further value translation to humans by combining in vitro cell culture systems and knockout mice with post-mortem MS brain analyses. The results of his project provide increased insights into the complex processes of CNS lesion development and repair, and aid in the quest for effective new strategies in the treatment of progressive MS.