220: Fibrinogen/CR3 signaling induces demyelination by promoting Th1 cell differentiation and peripheral macrophage recruitment into the CNS

Abstract

Blood–brain barrier (BBB) disruption, which allows the leakage and deposition of plasma proteins in the central nervous system (CNS), is a hallmark of multiple sclerosis (MS), a chronic autoimmune disease of the CNS characterized by activation of innate and adaptive immune responses. However, the contribution of increased vascular permeability to the development of autoimmunity remains unclear. Here we show that the plasma protein fibrinogen, the physiological ligand of complement receptor 3 (CR3) that is abundant in early and late MS lesions, can spontaneously induce inflammatory demyelination by triggering encephalitogenic T cell responses and macrophage recruitment into the CNS. By a single stereotactic injection in myelinated areas of healthy brain or spinal cord, we demonstrate that fibrinogen induces microglial activation, followed by infiltration of T cells and peripheral macrophages, leading to the development of demyelinating lesions. Demyelination upon fibrinogen injection is reduced in MHCII −/− and lymphocyte-deficient Rag2 −/− γ c −/− mice. Furthermore, co-culture of fibrinogen-treated bone-marrow-derived macrophages with T cells showed that fibrinogen specifically regulates T H 1 cell differentiation. In accordance, studies in myelin oligodendrocyte glycoprotein-specific (2D2) mice revealed that fibrinogen-induced inflammatory demyelination depends upon the recruitment of encephalitogenic T-cells. Genetic depletion or pharmacologically blocking of CR3 attenuated T H 1 cell differentiation, chemokine gene expression, peripheral macrophage recruitment, and inflammatory demyelination upon fibrinogen injection. Our data suggest that fibrin/CR3 signaling is an upstream regulator of the immune attack on the CNS by encephalitogenic T cells and peripheral macrophages. Our study identifies fibrinogen as a molecular link between increased vascular permeability and CNS autoimmunity, and introduces fibrinogen-induced encephalomyelitis (FIE) as an innate immune-driven animal model for MS.