Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS
Emiliano Trias, … , Olivier Hermine, Luis Barbeito
Emiliano Trias, … , Olivier Hermine, Luis Barbeito
Published October 4, 2018
Citation Information: JCI Insight. 2018;3(19):e123249. https://doi.org/10.1172/jci.insight.123249.
View: Text | PDF
Research Article Inflammation Neuroscience

Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS

  • Text
  • PDF
Abstract

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.

Authors

Emiliano Trias, Peter H. King, Ying Si, Yuri Kwon, Valentina Varela, Sofía Ibarburu, Mariángeles Kovacs, Ivan C. Moura, Joseph S. Beckman, Olivier Hermine, Luis Barbeito

×

Figure 1

Mast cells infiltrate into and degranulate in skeletal muscle of ALS patients.

Options: View larger image (or click on image) Download as PowerPoint
Mast cells infiltrate into and degranulate in skeletal muscle of ALS pat...
(A) Representative images of toluidine blue staining showing the infiltration of mast cells into quadriceps muscles of ALS patients. Upper panels are low-magnification microphotographs showing the significant infiltration of mast cells (arrows) into degenerating muscle of ALS patients compared with controls, where few mast cells are observed and mostly associated with blood vessels. Note the significant infiltration and degranulation state of mast cells in ALS conditions (lower panels). The graph shows the quantitative analysis of mast cells into the quadriceps muscles of 5 ALS patients and 5 controls stained with toluidine blue. The graph inset shows the quantitative analysis of mast cell infiltration for pooled ALS patients compared with pooled controls. Data were analyzed by Kruskal-Wallis followed by Dunn’s multiple-comparisons test (graph) and Mann-Whitney test, 2-tailed (graph inset), and expressed as mean ± SEM; P < 0.05 was considered statistically significant. (B) Representative confocal tile reconstruction showing chymase-positive mast cells (green, arrows) infiltrating quadriceps muscles from ALS and control donors. A marked infiltration of mast cells is seen in ALS patients when compared with controls, where few smaller chymase-positive mast cells are observed associated mostly with blood vessels. Dotted lines delimit myofibers. Scale bars: 100 μm. (C) Representative confocal microphotographs showing an important number of chymase-positive cells that show an irregular shape corresponding to a degranulating state, which is not observed in any of the controls analyzed. Scale bar: 10 μm. (D) Confocal microphotographs show the coexpression of the tyrosine kinase receptor c-Kit (red) and chymase (green) in a subpopulation of cells that resemble mast cell progenitors that infiltrate the muscle. Insets show 3D confocal reconstruction of separated channels. Scale bars: 5 μm (colocalization) and 10 μm (insets).

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts