P77: NADPH Oxidase Type 4 Inhibits Immune Cell Trafficking into The Central Nervous System During Neuroinflammation

Transendothelial trafficking of immune cells into the central nervous sys tem (CNS) and disruption of the blood brain barrier (BBB) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Accumulating evidence sugges t that oxidative s tress plays a major role in the pathogenesis of MS, whereas a specific influence of oxidative s tress on BBB dysfunction in MS was unclear so far. Here, we identify NADPH oxidase type 4 (NOX4) as a specific and direct modulator of BBB integrity. Deficiency of NOX4, but not NOX1 or NOX2, rendered mice more susceptible to experimental autoimmune encephalomyelitis (an animal model of MS) and was accompanied by a remarkable enhancement of BBB disruption and CNS inflammation. Murine and human in vitro analysis revealed that lack of NOX4 amplifies leukocyte trafficking by modified endothelial cells. Further, reduced endothelial NOX4 expression was found in CNS tissue of individuals suffering from MS indicating an important role of NOX4 also in humans. Our s tudy demons trates, for the firs t time, that NOX4 is an important and direct regulator of BBB integrity. NOX4 activation can decrease BBB damage and cell invasion during neuroinflammation and may offer a novels trategy for the treatment of MS.