Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.

The blood-brain barrier (BBB) is formed primarily to protect the brain microenvironment from the influx of plasma components, which may disturb neuronal functions. The BBB is a functional unit that consists mainly of specialized endothelial cells (ECs) lining the cerebral blood vessels, astrocytes and pericytes. The BBB is a dynamic structure that is altered in neurologic diseases, such as stroke. ECs and astrocytes secrete extracellular matrix (ECM) proteins to generate and maintain the basement membranes (BMs). ECM receptors, such as integrins and dystroglycan are also expressed at the brain microvasculature and mediate the connections between cellular and matrix components in physiology and disease. ECM proteins and receptors elicit diverse molecular signals that allow cell adaptation to environmental changes, and regulate growth and cell motility. The composition of the ECM is altered upon BBB disruption and directly affects the progression of neurologic disease. The purpose of this review is to discuss the dynamic changes of ECM composition and integrin receptor expression that control BBB functions in physiology and pathology.

Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b+ antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.