Microglia
Microglia are the main immune cells of the CNS (Fujita and Kitamura, 1975; Hickey and Kimura, 1988; Lawson et al., 1990). In ALS patients, activated microglia increase in CNS regions that are susceptible to neurodegeneration (Kawamata et al., 1992) and in SOD1G93A mice, enhanced microglial reactivity precedes nerve denervation at the NMJ (Alexianu et al., 2001; Saxena et al., 2009). Microglia exist in both resting and activated states [reviewed in Perry and Holmes (2014)] and in ALS, activated microglia display two distinct phenotypes. The neuroprotective M2 phenotype promotes tissue repair and supports MN survival by releasing neuroprotective factors, and the toxic M1 phenotype produces cytokines, enhances inflammation, and induces cell death (Liao et al., 2012). Studies in mutant SOD1 mice reveal that the numbers of microglia increase during disease progression, but they vary between the neuroprotective M2 and toxic M1 phenotypes (Liao et al., 2012; Chiu et al., 2013). In lumbar spinal cords of pre-symptomatic SOD1G93A mice, the anti-inflammatory M2 microglia predominate (Gravel et al., 2016), whereas at disease onset and during progression, the proinflammatory M1 type is more common (Beers et al., 2011). Microglial-specific ablation of mutant SOD1G37R in mice does not affect disease initiation, but it significantly slows disease progression (Boillée et al., 2006b), indicating that microglia enhance the progression, but not the onset, of disease in transgenic mutant SOD1 mice. However, contradictory findings were obtained in the TDP-43 rNLS8 model, where microglia were neuroprotective and not neurotoxic (Spiller et al., 2018). Interestingly, knockdown of C9orf72 in mice alters microglial function and induces age-related neuroinflammation, but not neurodegeneration (Lall and Baloh, 2017). Further investigations are required to examine the role of microglia in other ALS disease models, and to determine whether MN subtypes display different vulnerabilities to microglia-mediated protective and/or toxicity in ALS.