Abstract
While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases.
Highlights
Once considered an immune-privileged site because of the presence of the blood brain barrier (BBB), it is clear that while peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults [1]
Persistent activation of brain-resident microglia may increase the permeability of the BBB and promote increased infiltration of peripheral macrophages, the phenotype of which is critically determined by the CNS environment [10]
Most recently in what is the largest and longest duration epidemiological study to date, long-term (> 5 yrs) non-steroidal anti-inflammatory drugs (NSAIDs) use, in particular ibuprofen, was shown to be protective against development of Alzheimer's disease (AD) [50]. These findings suggest that the protection afforded by chronic NSAID use in the studies of AD patients may in part be derived by attenuation of microglia activation
Summary
It is becoming increasingly evident that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative diseases. While neuroinflammation and microglia provide an attractive therapeutic target in the treatment and prevention of neurodegenerative diseases investigators face several challenges ahead (Appendix 2) which must be overcome before one can advocate in favor of large-scale anti-inflammatory trials in the clinic. Some of these include developing approaches to improve the access of drugs to CNS tissue as well as developing therapies that maintain or optimize the beneficial effects of neuroinflammation while eliminating or minimizing its detrimental effects
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