Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

Trías, Emiliano; Ibarburu, Sofía; Barreto-Núñez, Romina; Varela, Valentina; Moura, Ivan C.; Dubreuil, Patrice; Hermine, Olivier; Beckman, Joseph S.; Barbeito, Luis

doi:10.1172/jci.insight.95934

Cited by 63 publications

(69 citation statements)

References 75 publications

(99 reference statements)

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“…All rats were weighed and evaluated for motor activity daily as described (Trias et al, , ). Disease onset was determined for each animal when pronounced muscle atrophy was accompanied by an abnormal gait, typically expressed as subtle limping or dragging of one hind limb.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously (Trias et al, , ), only transgenic rats showing weakness and gait alterations in hind limbs as the first clinical sign were selected for masitinib treatment studies. Male rats were divided randomly into the masitinib or vehicle‐treated groups.…”

Section: Methodsmentioning

confidence: 99%

“…Masitinib mesylate (AB1010), freshly prepared in drinking sterilized water, was administrated daily at a dose of 30 mg/kg using a curved stainless steel gavage needle with 3‐mm ball tip. Dosing was defined in accordance to previous studies in the same rat model of ALS that was shown to be safe for chronic treatments (Trias et al, , ). Rats were treated from Day‐1 postparalysis for an additional 15 days, when they were then euthanized.…”

Section: Methodsmentioning

confidence: 99%

“…CSF‐1R and c‐Kit are typically expressed in myeloid cells and mast cells, respectively (Galli, Tsai, & Wershil, ; Stanley & Chitu, ). In SOD1 G93A rats developing paralysis, masitinib downregulates mast cells and neutrophil infiltration in both the sciatic nerve and skeletal muscle motor nerve terminals (Trias et al, ; Trias et al, ). In addition, masitinib decreases CSF‐1R‐dependent microgliosis in the lumbar spinal cord, suggesting a multitarget and multifaceted effect involving various inflammatory pathways in the central and peripheral nervous systems (Trias et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…SCF/c‐Kit signaling drives chemoattraction of mast cell precursors, their differentiation into mature mast cells and ultimate degranulation, with the release of inflammatory and vasoactive molecules (Galli et al, ). Mast cells are key in orchestrating chronic inflammation and immune cell infiltration (Metz et al, ) and recently have been reported to extensively infiltrate the muscle and sciatic nerve of ALS patients and SOD1 G93A rats (Trias et al, ; Trias et al, ). The cellular sources of CSF1, IL‐34, and SCF in ALS peripheral nerves remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Trías

Kovacs

King

et al. 2019

Glia

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Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian‐like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1G93A rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100β, GFAP, isolectin and/or p75NTR immunoreactivity. Different subsets of reactive SCs expressed colony‐stimulating factor‐1 (CSF1) and Interleukin‐34 (IL‐34) and closely interacted with numerous endoneurial CSF‐1R‐expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c‐Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c‐Kit in the sciatic nerves of SOD1G93A rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c‐Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF‐1R and c‐Kit with masitinib in SOD1G93A rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Trías

Kovacs

King

et al. 2019

Glia

Self Cite

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New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the ‘dying back’ hypothesis

Sbarigia,

Rome,

Dini

et al. 2024

J of Extracellular Bio

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Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, and is characterized by muscle weakness, paralysis and ultimately, respiratory failure. The exact causes of ALS are not understood, though it is believed to combine genetic and environmental factors. Until now, it was admitted that motor neurons (MN) in the brain and spinal cord degenerate, leading to muscle weakness and paralysis. However, as ALS symptoms typically begin with muscle weakness or stiffness, a new hypothesis has recently emerged to explain the development of the pathology, that is, the ‘dying back hypothesis’, suggesting that this degeneration starts at the connections between MN and muscles, resulting in the loss of muscle function. Over time, this damage extends along the length of the MN, ultimately affecting their cell bodies in the spinal cord and brain. While the dying back hypothesis provides a potential framework for understanding the progression of ALS, the exact mechanisms underlying the disease remain complex and not fully understood. In this review, we are positioning the role of extracellular vesicles as new actors in ALS development.

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Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence

Hamad,

Amer,

Hawas

et al. 2023

Neurol Sci

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Objectives Masitinib, originally developed as a tyrosine kinase inhibitor for cancer treatment, has shown potential neuroprotective effects in various neurological disorders by modulating key pathways implicated in neurodegeneration. This scoping review aimed to summarize the current evidence of masitinib’s neuroprotective activities from preclinical to clinical studies. Methods This scoping review was conducted following the guidelines described by Arksey and O’Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria covered all original studies reporting on the neuroprotective effects of masitinib, including clinical studies, animal studies, and in vitro studies. Results A total of 16 studies met the inclusion criteria and were included in the review. These comprised five randomized controlled trials (RCTs), one post-hoc analysis study, one case report, and nine animal studies. The RCTs focused on Alzheimer’s disease (two studies), multiple sclerosis (two studies), and amyotrophic lateral sclerosis (one study). Across all included studies, masitinib consistently demonstrated neuroprotective properties. However, the majority of RCTs reported concerns regarding the safety profile of masitinib. Preclinical studies revealed the neuroprotective mechanisms of masitinib, which include inhibition of certain kinases interfering with cell proliferation and survival, reduction of neuroinflammation, and exhibition of antioxidant activity. Conclusion The current evidence suggests a promising therapeutic benefit of masitinib in neurodegenerative diseases. However, further research is necessary to validate and expand upon these findings, particularly regarding the precise mechanisms through which masitinib exerts its therapeutic effects. Future studies should also focus on addressing the safety concerns associated with masitinib use.

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Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

Cited by 63 publications

References 75 publications

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the ‘dying back’ hypothesis

Masitinib as a neuroprotective agent: a scoping review of preclinical and clinical evidence

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