Regulation of extracellular proteolysis by microglia and brain-infiltrating macrophages during neuroinflammation

Neuroinflammation is characterized by the activation of brain cells and local release of mediators following an inflammatory challenge. When persisting, it leads to demyelination of the central nervous system (CNS), a prevalent process in multiple sclerosis or acquired CNS demyelinating syndromes. Several studies have implicated extracellular proteases and their endogenous regulators, including broad spectrum inhibitors, specific inhibitors, inducers and clearance receptors in neuroinflammation and neurodegeneration. We hypothesize that during neuroinflammation, these molecules and their interplay with proteolytic enzymes can determine disease outcomes, such as the occurrence of onset/relapse and remission phases in MS. We will investigate extracellular protease regulation mechanisms in microglia and (brain-infiltrating) macrophages in in vitro and in vivo models for neuroinflammation and demyelination, and we will validate our obtained results in samples from patients with CNS demyelinating disorders. The outcome of the proposed research has the potential for discovery of new disease targets and diagnostic or prognostic markers.