Inflammatory mechanisms in chronic neurodegenerative disease: the impact of microglia priming

Perry, V. Hugh (2013) Inflammatory mechanisms in chronic neurodegenerative disease: the impact of microglia priming. In, Stevens, Robert D., Sharshar, Tarek and Ely, E. Wesley (eds.) Brain Disorders in Critical Illness: Mechanisms, Diagnosis, and Treatment. Cambridge University Press, pp. 172-180. (doi:10.1017/CBO9781139248822.021).

Abstract

Microglia, the resident macrophages of the central nervous system (CNS), have a relatively down-regulated phenotype when compared with other tissue macrophages. The CNS exerts an inhibitory influence on the microglia phenotype via neuronal expression of ligands which impact on receptors on the microglia. The loss or degeneration of neurons leads to activation of microglia as detected by changes in morphology and up-regulation, or <italic>de novo</italic> synthesis, of a spectrum of myeloid-related molecules. During chronic neurodegenerative disease in animal models the microglia are increased in number, have an activated morphology, but express an anti-inflammatory phenotype. In naïve animals a systemic inflammatory challenge leads to communication with the brain and is part of our defense against injury and infection. The macrophage populations of the brain are involved in signaling from the peripheral immune system to CNS neurons. A systemic inflammatory challenge in an animal with ongoing chronic neurodegeneration leads to switching of the microglia to a pro-inflammatory phenotype with the capacity to disrupt neuronal function and cause tissue degeneration. We propose that the impact of systemic inflammation on microglia primed by prior pathology, and their switching to an aggressive tissue-damaging phenotype, may underlie clinical observations that systemic inflammation in patients with Alzheimer’s disease is associated with exacerbation of symptoms and acceleration in cognitive decline. The concept of microglia priming and secondary activation by systemic inflammation may have relevance to diverse neurological conditions and highlights the importance of prompt treatment of systemic infection and inflammation in patients with acute or chronic neurodegeneration.

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