Figure 1. Inflammatory dynamics follow a stereotyped pattern in neuroinflammatory disorders.

Upper portion describes neuroinflammatory events, whereas lower portion depicts immune cell responses over time. In healthy tissue, quiescent microglia and astrocytes sample the local CNS microenvironment for signs of infection or damage. Neuroinflammation can be initiated by trauma (brain or spinal cord injury), ischemia, infection, aging, or unknown causes. Microglia and astrocytes detect the immune stimulus and respond by becoming activated, proliferating, and releasing cytokines/chemokines. These cytokines/chemokines cause peripheral immune cells (which usually have limited CNS access) to translocate into CNS parenchyma. Initially, neutrophils and macrophages (and likely dendritic cells) – cells of the innate immune system – enter the CNS compartment. Macrophages in particular persist in the CNS for long periods and maintain a potentially cytotoxic pro-inflammatory phenotype. Since the blood-brain barrier (BBB) becomes more permeable and new antigens become exposed with CNS damage (e.g., inner portions of myelin), CNS antigens may be newly presented to naïve cells of the adaptive immune system (acute-mid-stage neuroinflammation). Many of these antigens may not have been presented outside the CNS before, so CNS antigen-specific adaptive immune cells may exist and undergo clonal expansion during neuroinflammation. At mid-stage to chronic neuroinflammation, these potentially autoreactive T cells and B cells translocate into the CNS parenchyma. A strong adaptive response to non-resolving neuroinflammation could exacerbate pathology. The course of neuroinflammatory dynamics is similar in traumatic, ischemic, autoimmune, and neurodegenerative disorders.