Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss. While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease. On these grounds, many treatments have been tested on ALS animals with the aim of inhibiting or reducing the pro-inflammatory action of microglia and astrocytes and counteract the progression of the disease. Unfortunately, these anti-inflammatory therapies have been only modestly successful. The non-univocal role played by microglia during stress and injuries might explain this failure. Indeed, it is now well recognized that, during ALS, microglia displays different phenotypes, from surveillant in early stages, to activated states, M1 and M2, characterized by the expression of respectively harmful and protective genes in later phases of the disease. Consistently, the inhibition of microglial function seems to be a valid strategy only if the different stages of microglia polarization are taken into account, interfering with the reactivity of microglia specifically targeting only the harmful pathways and/or potentiating the trophic ones. In this review article, we will analyze the features and timing of microglia activation in the light of M1/M2 phenotypes in the main mice models of ALS. Moreover, we will also revise the results obtained by different anti-inflammatory therapies aimed to unbalance the M1/M2 ratio, shifting it towards a protective outcome.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss
While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease
Transgenic superoxide dismutase 1 (SOD1) mice are so far the most widely used model to study ALS. Both active (SOD1G93A, SOD1G37R) and inactive (SOD1G85R) mutants show a phenotype characterized by a progressive paralysis and death, caused by degeneration of motoneurons, and exhibit gliosis within the spinal cord, brain stem and cortex (Philips and Rothstein, 2015), suggesting that neurodegeneration relies on a gain of toxic function of the protein
Summary
Amyotrophic lateral sclerosis (ALS) is a multifactorial disease caused by genetic and non-inheritable components leading to motoneuron degeneration in the spinal cord, brain stem and primary motor cortex (Al-Chalabi and Hardiman, 2013). It is indicated as ‘‘surveillant’’ microglia and participates to many physiological functions, including synaptic pruning, adult neurogenesis and modulation of neuronal networks (Walton et al, 2006; Kettenmann et al, 2013) This highly specific interaction with the extracellular environment is tightly regulated (Nimmerjahn et al, 2005; Parisi et al, 2016b), these cells rapidly react to abnormalities, adopting a less ramified/amoeboid phenotype, corresponding to activated microglia (Luo and Chen, 2012; FIGURE 1 | M1/M2 microglia polarization during amyotrophic lateral sclerosis (ALS)-induced motor neuron degeneration. ‘‘alternatively activated’’ M2 phenotype, which is induced by anti-inflammatory cytokines IL-4, IL-10 or IL-13, suppresses inflammation, clears cellular debris through phagocytosis, promotes extracellular matrix reconstruction and supports neuron survival through the release of protective/trophic factors (Hu et al, 2015; Du et al, 2016; Tang and Le, 2016). ‘‘Acquired deactivation’’ represents another M2 anti-inflammatory phenotype and it is mainly induced by the uptake of apoptotic cells or exposure to anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β (Tang and Le, 2016)
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