Figure 3.

Complement and coagulation cascade neuroinflammatory effects on the node of Ranvier (NOR): (A) Peripheral nervous system (PNS) NOR: Schwann cells express protease-activating receptor 1 (PAR1) at the microvilli. Neurofascin-186 (NF-186) interacts with gliomedin in the matrix and in the microvilli to promote axon–Schwann cell microvilli attachment. Neurofascin-155 (NF-155), a paranodal protein, acts as a cell adhesion molecule between axons and myelin. In physiological conditions, complement and coagulation factors are downregulated in the PNS. C1q is bound to myelin-associated glycoprotein (MAG), a transmembrane glycoprotein localized in Schwann cells and oligodendrocytes. (B) Central nervous system (CNS) NOR: Normal myelin thickness and gaps at the NOR are mediated by astrocyte exocytosis. PAR1 is localized on the cell body and astrocytic endfeet. Thrombin is generated by neuronal and glial cells. (C) PNS NOR pathology: Complement activation and membrane attack complex (MAC) formation are upregulated in pathophysiological conditions. MAC mediates the cell-killing effect of the complement cascade. The NOR is a primary site of immune attack. Anti-NF186 and NF-155 antibodies have been found in PNS demyelinating disorders. In the PNS, thrombin levels increased in diseased states. NOR morphology was damaged and nerve conduction velocity was impaired. (D) CNS NOR pathology: A plausible role of the complement system as a part of the coagulation–inflammation interface is suggested. Thrombin proteolysis of NF-155 has negative effects on axonal conduction. Inhibitors of thrombin activity such as protease nexin 1 (PN1) are locally expressed in the brain. Perinodal astrocytes regulate this mechanism by secreting PN1. Illustration created with BioRender.com. Accessed date: 16 December 2021.