Astrogliosis in CNS pathologies: is there a role for microglia?

Abstract

Astrogliosis, a cellular reaction with specific structural and functional characteristics, represents a remarkably homotypic response of astrocytes to all kinds of central nervous system (CNS) pathologies. Astrocytes play diverse functions in the brain, both harmful and beneficial. Mounting evidence indicates that astrogliosis is an underlying component of a diverse range of diseases and associated neuropathologies. The mechanisms that lead to astrogliosis are not fully understood, nevertheless, damaged neurons have long been reported to induce astrogliosis and astrogliosis has been used as an index for underlying neuronal damage. As the predominant source of proinflammatory factors in the CNS, microglia are readily activated under certain pathological conditions. An increasing body of evidence suggests that release of cytokines and other soluble products by activated microglia can significantly influence the subsequent development of astrogliosis and scar formation in CNS. It is well known that damaged neurons activate microglia very quickly, therefore, it is possible that activated microglia contribute factors/mediators through which damaged neuron induce astrogliosis. The hypothesis that activated microglia initiate and maintain astrogliosis suggests that suppression of microglial overactivation might effectively attenuate reactive astrogliosis. Development of targeted anti-microglial activation therapies might slow or halt the progression of astrogliosis and, therefore, help achieve a more beneficial environment in various CNS pathologies.

Fig. 1

Microglial activation precedes astrogliosis after neuronal damage induced by MPP⁺. Primary mixed neuron-glial cultures from rats were treated with 0.5 µM MPP⁺. At different time points after MPP⁺ challenge, Iba-1 and GFAP protein expression were evaluated as markers of microglial and astrocyte activation, respectively. a At different time points after MPP⁺ treatment, Iba-1 protein expression was assayed using Western blot. b Quantitative analysis of Iba-1 protein expression. Data have been normalized to GAPDH expression. c At different time points after MPP⁺ treatment, GFAP protein expression was assayed using ELISA. Data are mean±SEM of three experiments performed in triplicate. *p<0.05, compared with corresponding control cultures

Fig. 2

Proinflammatory factors from activated microglia are triggers and modulators of astrogliosis. Insults such as neurotoxins, infections, and trauma to the CNS can directly trigger neuronal damage. Injured neurons can activate the surrounding microglia and astrocyte and induce further glial reaction. Compared with astrocyte, microglia are more sensitive, more readily activated and undergo a dramatic transformation from their resting ramified state into an amoeboid morphology. In their activated state, microglia can release a diverse set of proinflammatory factors, such as cytokines, eicosanoids, chemokines, reactive free radicals and proteases. These inflammatory mediators not only can further modulate microglial activity but also can have a very important influence on surrounding astrocytes. The proinflammatory mediators can induce astrogliosis through their receptors on astrocyte, thus serve the function of triggers and modulators of astrogliosis