TitleMast cells and neutrophils mediate peripheral motor pathway degeneration in ALS.
Publication TypeJournal Article
Year of Publication2018
AuthorsTrias E, King PH, Si Y, Kwon Y, Varela V, Ibarburu S, Kovacs M, Moura IC, Beckman JS, Hermine O, Barbeito L
JournalJCI Insight
Date Published2018 10 04

Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.

Alternate JournalJCI Insight
PubMed ID30282815
PubMed Central IDPMC6237484
Grant ListI01 BX001148 / BX / BLRD VA / United States
R01 NS092651 / NS / NINDS NIH HHS / United States