Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS
| Autor: | Mariángeles Kovacs, Joseph S. Beckman, Ying Si, Ivan C. Moura, Olivier Hermine, Peter H. King, Valentina Varela, Sofía Ibarburu, Yuri Kwon, Emiliano Trias, Luis Barbeito |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Neutrophils Pyridines Neuromuscular Junction Inflammation Neuromuscular junction Cell Degranulation Extensor digitorum longus muscle 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Superoxide Dismutase-1 Piperidines Medicine Animals Humans Mast Cells Amyotrophic lateral sclerosis Muscle Skeletal Protein Kinase Inhibitors Neuroinflammation Denervation Motor Neurons business.industry Superoxide Dismutase Masitinib Amyotrophic Lateral Sclerosis General Medicine Mast cell medicine.disease Axons Rats Disease Models Animal Thiazoles 030104 developmental biology medicine.anatomical_structure Treatment Outcome chemistry Neutrophil Infiltration Benzamides medicine.symptom Rats Transgenic business 030217 neurology & neurosurgery Research Article |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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