Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS

JCI Insight. 2018 Oct 4;3(19):e123249. doi: 10.1172/jci.insight.123249.


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.

Keywords: ALS; Inflammation; Mast cells; Neuroscience; Neutrophils.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / immunology*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Axons / drug effects
  • Axons / immunology
  • Axons / pathology
  • Benzamides
  • Cell Degranulation / drug effects
  • Cell Degranulation / immunology
  • Disease Models, Animal
  • Humans
  • Male
  • Mast Cells / drug effects
  • Mast Cells / immunology*
  • Motor Neurons / cytology
  • Motor Neurons / immunology
  • Motor Neurons / pathology*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / pathology
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / immunology
  • Neuromuscular Junction / pathology*
  • Neutrophil Infiltration / drug effects
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Piperidines
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines
  • Rats
  • Rats, Transgenic
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1 / genetics
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use
  • Treatment Outcome


  • Benzamides
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridines
  • SOD1 protein, human
  • Thiazoles
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • masitinib