Inhibition of activated protein C dramatically attenuated experimental autoimmune encephalomyelitis (164.9)

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. Given that the major pathological component of multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis (EAE), is the extravasation of autoreactive immune cells in the central nervous system (CNS) due to blood brain barrier (BBB) dysfunction, we investigated whether APC can affect the progression of EAE. We saw that blocking endogenous APC during EAE resulted in considerable immune cell infiltration in the CNS. 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 cytokine profile of leukocytes from the anti-APC mice was skewed to T helper-2, which is known to be protective in EAE. These data show 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.