How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

Abnormal immune response/inflammation is present in patients of amyotrophic lateral sclerosis (ALS). Autoimmune-related inflammation has been thought to be involved in the pathogenesis of ALS. However, how the abnormal immune responses are initiated, what specific immune cells and how these immune cells are involved in this disease have not been well understood. This is partly owing to two facts of ALS: late diagnosis and chronic nature. The late diagnosis makes it difficult to conclude whether the abnormal immune responses/inflammation is the cause or result of the disease. The chronic nature makes it difficult to determine the best timing for the detection of such autoimmune responses. To resolve these two challenges for research, the authors introduced motor nerve injury (facial nerve axotomy, FNA) into a pre-symptomatic mouse ALS model (8-week-old SOD1G93A mice), which induces a readily detectable immune response in a predictable time period (3-14 days). The authors found that pre-symptomatic SOD1G93A mice showed a higher basal level of T cell activation and Th17 cells than WT mice, which can be further increased by FNA. However, why these pro-inflammatory Th lymphocyte subsets are preferentially elicited in ALS has been elusive. Recently, several studies support that the programmed necrosis (necroptosis), a new type of cell death, is present in ALS. Because necroptosis results in the release of pro-inflammatory stimuli, we speculate that initial motoneuron (MN) necroptosis may be the cause of abnormal immune responses in the development of ALS, and subsequently, inflammation/immune response serve as an amplifier to cause more MN death. Here, the authors reviewed recent studies concerning the type of MN death, the inflammation/immune responses and the research strategies for ALS. With the available evidences from the literature, the authors present a hypothesized working model to indicate the possible connections among necroptosis, immune responses and MN death in the development of ALS and suggest the future studies for searching the potential therapy for ALS