PURPOSE OF REVIEW: Neuroinflammation is an important mediator of the 
pathogenesis of disease in amyotrophic lateral sclerosis (ALS). Genetic 
mutations such as C9orf72 have begun to define the numerous cell autonomous 
pathways that initiate motor neuron injury. Yet, it is the signalling to 
surrounding glia and peripherally derived immune cells that initiates the 
noncell autonomous inflammatory process and promotes self-propagating motor 
neuron cell death. The purpose of this review is to explore the systemic 
immune/inflammatory contributions to the pathogenesis of ALS: what are the 
peripheral pro-inflammatory signatures, what initiates their presence and do 
they represent potential therapeutic targets.
RECENT FINDINGS: In ALS, motor neuron cell death is initiated by multiple cell 
autonomous pathways leading to misfolded proteins, oxidative stress, altered 
mitochondria, impaired autophagy and altered RNA metabolism, which collectively 
promote noncell autonomous inflammatory reactivity. The resulting disease is 
characterized by activated microglia and astrocytes as well as peripherally 
derived pro-inflammatory innate and adaptive immune cells. In this unrelenting 
disorder, circulating blood monocytes and natural killer cells are 
pro-inflammatory. Furthermore, regulatory T lymphocytes are dysfunctional, and 
pro-inflammatory cytokines and acute phase proteins are elevated.
SUMMARY: The collective dysregulation of cells and cytokines in patients with 
ALS accurately reflect increased disease burdens, more rapid progression rates 
and reduced survival times, reinforcing the concept of ALS as a disorder with 
extensive systemic pro-inflammatory responses. These increased systemic 
pro-inflammatory immune constituents provide potentially meaningful therapeutic 
targets.