Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration

Abstract

Microglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as 'microglial priming', seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS.

Fig. 1

Microglia in the naïve mouse brain express CD11b (a) and CD68 (c). In an animal with a chronic neurodegenerative disease, prion disease, the microglia increase in number and become activated, altering their morphology with upregulation of CD11b (b) and CD68 (d). Scale bar in a, b = 20 μm, c, d = 10 μm

Fig. 2

Electron micrograph of a microglia cell in the mouse brain labelled with F4/80. Note the sparse cytoplasm and limited organelles typical of the down-regulated phenotype of microglia. Ligands expressed by neurons (left column) bind receptors on microglia (right column) that inhibit their activation

Fig. 3

Communication between the CNS and the immune system contributes to homeostasis during systemic inflammation, resulting in transient, reversible microglial activation and adaptive behavioural and metabolic changes. Normal ageing and low-grade systemic inflammation result in prolonged ‘priming’, microglial activation. We hypothesize that multiple or chronic systemic inflammation not only accelerates the normal ageing process, resulting in irreversible pathological changes in the CNS, but may also contribute to neuronal dysfunction, disease symptoms and disease progression in the diseased CNS