Local tissue Transglutaminase activity directs experimental Multiple Sclerosis pathology

A critical pathogenic aspect of multiple sclerosis (MS) is the influx of immunomodulatory cells into the central nervous system (CNS) leading to neurological deficits. We here provide evidence that tissue Transglutaminase (TG2) is an attractive therapeutic target for MS that, in contrast to other MS therapies, is acting locally. During MS and its animal model chronic-relapsing EAE (cr-EAE), TG2 levels are significantly increased and reduction of TG2 activity in cr-EAE animals dramatically attenuated clinical deficits. The mechanism underlying the clinical beneficial effects points toward a reduction in monocyte migration into the CNS due to attenuated monocytic cytoskeletal flexibility and RhoA GTPase activity. We conclude that reduction of TG2 activity opens new avenues for therapeutic intervention in MS.