Activated immune response in the peripheral nervous system is instrumental to delay the disease progression in ALS mouse models

The role of the immune system on the progression of amyotrophic lateral sclerosis (ALS) is still controversial being considered either pathogenic or beneficial depending on the context in which it is examined. Recently, we demonstrated that motorneurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This phenomenon occurs to a lesser extent in 129SvSOD1G93A mice that show a faster disease progression despite expressing the same amount of mutant SOD1 (1). Unexpectedly, neuropathological differences between the fast and slow progressing mice were not found in the loss of lumbar spinal MNs perikaria but rather in the axonal and neuromuscular compartments (2,3). Objective: The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of ALS with a less severe disease course. Methods:The extent of axonal damage, Schwann cell proliferation and neuromuscular junctions (NMJs) denervation were compared between the two ALS mouse models at the disease onset using immunohistochemical and imaging techniques. Then we compared the expression levels of different immune molecules and the presence of blood derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot and qRT-PCRtechniques. Results: Muscle denervation, axonal dysregulation, myelin disruption together with a reduced Schwann cell proliferation is prominent in 129SvSOD1G93A compared to C57SOD1G93A mice. This correlates with the faster progression of the disease observed in the first strain. On the contrary, a striking increase of immune molecules,such as CCL2, MHCI and C3, was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8 + T lymphocytes and macrophages. These phenomena were barely or not detectable in the peripheral nervous system of fast progressing mice. Discussion and conclusions:These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system in order to delay muscle denervation and prolong the lifespan. Thereby, the lack of this response has a negative impact on the disease course.