Does neuroinflammation fan the flame in neurodegenerative diseases? - PubMed (original) (raw)

Does neuroinflammation fan the flame in neurodegenerative diseases?

Tamy C Frank-Cannon et al. Mol Neurodegener. 2009.

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.

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Figures

Figure 1

Figure 1

Neuroinflammation can precede and contribute to neuronal dysfunction and degeneration. Divergent initiating triggers directly or indirectly converge to activate microglia (stained here with an antibody against F4/80) from a ramified/resting state to an ameboid-shape/activated state, initiating a self-propelling cycle of neuroinflammation and chronic over-production of inflammatory mediators. These mediators impact susceptible neuronal populations in the CNS and contribute to their demise within the context of each neurodegenerative disorder. The progressive loss of neurons that characterizes these disorders further contributes to generation of debris and keeps microglia activated indefinitely maintaining microglia in an activated state long-term.

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