The question of whether neuroinflammation is helpful or harmful in ALS is complex and likely determined by a number of factors across the clinical, cellular and molecular levels of the disease. The clinical asynchrony of ALS compounds this complexity, with different cells affected at different times and to different extents. Microglia are unlikely to be the main cell type driving motor neuron death in ALS but may still play an important modulatory role. Both neuroprotective and neurotoxic roles of microglia may co-exist in models of the disease (Liao et al., 2012; Chiu et al., 2013). It is likely that microglia adopt an M2-like neuroprotective state early in the disease but transition to M1-like toxic state as ALS progresses. Given the clinical, cellular and molecular heterogeneity, it is very likely that such transitions in microglial activation state will occur asynchronously.
The key issue of whether activation states of microglia are manipulable for tractable therapeutic benefit has yet to be systematically addressed. Previous trials using general immunosuppression or depleting specific arms of the immune system have not yet led to effective therapies (Crisafulli et al., 2018). Specifically targeting a combination of cytokines either directly or through modulating the activation status of microglia are potentially attractive therapeutic approaches. However, much about the role of microglia in ALS remains unknown. A multimodal approach encompassing in vitro and in vivo model systems, expressing different ALS causing mutations, will provide further insight concerning the involvement of microglia in ALS. As multiple cell types including astrocytes and peripheral immune cells impact upon microglial function in ALS, determining the mechanisms behind these interactions will provide a more comprehensive understanding of microglia in this disease. Furthermore, understanding the impact of normal ageing on microglia may be important in elucidating how age renders people vulnerable to ALS and other neurodegenerative diseases. Identifying both primary and secondary events in different cell types will help decode the cellular phase in ALS and may lead to polytherapies with a higher success rate in clinical trials.
ALS = amyotrophic lateral sclerosis
This work was supported by the Francis Crick Institute whichreceives its core funding from Cancer Research UK (FC0101 10), the UK Medical Research Council (FC010110), and the WellcomeTrust (FC010110). R.P. holds an MRC Senior Clinical Fellowship [MR/S006591/1].
Brain. 2020;143(12):3526-3539. © 2020 Oxford University Press