Inhibition of Activated Protein C Attenuated Experimental Autoimmune Encephalomyelitis (171.13)

Abstract

Abstract Activated Protein C (APC) is an anticoagulant that is involved in the complex two-way interactions between the coagulation and immune systems. APC is widely known to be anti-inflammatory; most notably it has been clinically developed for treatment of severe sepsis. The anti-inflammatory properties of APC include conferring endothelial barrier protection, thus limiting the extravasation of immune cells into tissues. We investigated whether APC can affect the progression of experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The major pathological component of EAE is blood brain barrier (BBB) dysfunction resulting in the extravasation of autoreactive immune cells into the central nervous system (CNS). We observed that inhibition of endogenous APC during EAE resulted in considerable immune cell infiltration in the brain. Interestingly, however, these mice exhibited mild to no outward signs of EAE as assessed by paralysis severity. The anti-APC treated mice also had significantly higher percentage of CD4+Foxp3+ cells both in the CNS and in the periphery compared to controls. Moreover, the frequency of cells characterized as myeloid derived suppressor cells are increased in anti-APC treated EAE mice. Our study shows that lowered APC levels during EAE can lead to divergent effects on EAE pathogenesis, specifically leading to increased BBB dysfunction while simultaneously inducing immunological conditions that are non-pathogenic in EAE.