Defining Neuroinflammation

In steady-state conditions, neuroinflammation is defined solely as a central nervous system (CNS) innate immune response that serves to control infection through microbial elimination. This, together with scavenging cell debris and misfolded proteins, controls disease. To such ends, neuroinflammatory processes play a significant role in CNS homeostasis in health and disease control. The immune system affects the development, maintenance, and sustenance of brain cells and their connections. Linked to aging, epidemiological, animal, human, and therapeutic studies support the roles of neuroinflammatory cascades in sustaining neural function. This is highlighted by the neurotoxic microglial potential. In a steady state, microglia serve to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of innate and adaptive immune responses. In neurodegenerative diseases, activated microglia affect neuronal injury and death through the production of glutamate, pro-inflammatory factors, reactive oxygen species, and quinolinic acid, amongst others, and by mobilization of adaptive immune responses and cell chemotaxis, leading to transendothelial migration of immunocytes across the blood–brain barrier and perpetuation of neural damage. While the CNS is considered immunologically unique, glial–neuronal interactions occur under homeostatic and pathological conditions, with the mechanisms of immune privilege now reevaluated. One reevaluation changed the concept of immune privilege with the now-defined lymphatic drainage of CNS antigens. Notably, as the disease progresses, inflammatory secretions engage neighboring glial cells, including astrocytes and endothelial cells, resulting in a vicious cycle of autocrine and paracrine amplification of inflammation, perpetuating tissue injury. Such pathogenic processes contribute to neurodegeneration. The research seeks to harness such inflammatory processes to develop therapeutic interventions that positively affect the tempo and progression of human disease.