Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS)

Autor: Michael G. Meyer, Jonathan M. Van Dyke, Masatoshi Suzuki, Corey Macrander, Dan Krakora, Ivy Smit-Oistad
Rok vydání: 2016
Předmět:
0301 basic medicine
Pathology
medicine.medical_specialty
animal structures
Glial Cell Line-Derived Neurotrophic Factor Receptors
Interleukin-1beta
Neuromuscular Junction
Schwann cell
Nerve Tissue Proteins
S100 Calcium Binding Protein beta Subunit
Biology
Neuromuscular junction
Article
03 medical and health sciences
0302 clinical medicine
Developmental Neuroscience
Neurotrophic factors
Antigens
CD
medicine
Glial cell line-derived neurotrophic factor
Animals
Receptors
Cholinergic
Glial Cell Line-Derived Neurotrophic Factor
Amyotrophic lateral sclerosis
Muscle
Skeletal
Inflammation
Glial fibrillary acidic protein
Superoxide Dismutase
Tumor Necrosis Factor-alpha
Macrophages
Amyotrophic Lateral Sclerosis
Skeletal muscle
Motor neuron
medicine.disease
Rats
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
nervous system
Neurology
biology.protein
Schwann Cells
Rats
Transgenic
Neuroscience
Neuroglia
030217 neurology & neurosurgery
Zdroj: Experimental Neurology. 277:275-282
ISSN: 0014-4886
DOI: 10.1016/j.expneurol.2016.01.008
Popis: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor dysfunction and loss of large motor neurons in the spinal cord and brain stem. While much research has focused on mechanisms of motor neuron cell death in the spinal cord, degenerative processes in skeletal muscle and neuromuscular junctions (NMJs) are also observed early in disease development. Although recent studies support the potential therapeutic benefits of targeting the skeletal muscle in ALS, relatively little is known about inflammation and glial responses in skeletal muscle and near NMJs, or how these responses contribute to motor neuron survival, neuromuscular innervation, or motor dysfunction in ALS. We recently showed that human mesenchymal stem cells modified to release glial cell line-derived neurotrophic factor (hMSC-GDNF) extend survival and protect NMJs and motor neurons in SOD1 G93A rats when delivered to limb muscles. In this study, we evaluate inflammatory and glial responses near NMJs in the limb muscle collected from a rat model of familial ALS (SOD1 G93A transgenic rats) during disease progression and following hMSC-GDNF transplantation. Muscle samples were collected from pre-symptomatic, symptomatic, and end-stage animals. A significant increase in the expression of microglial inflammatory markers (CD11b and CD68) occurred in the skeletal muscle of symptomatic and end-stage SOD1 G93A rats. Inflammation was confirmed by ELISA for inflammatory cytokines interleukin-1 β (IL-1β) and tumor necrosis factor-α (TNF-α) in muscle homogenates of SOD1 G93A rats. Next, we observed active glial responses in the muscle of SOD1 G93A rats, specifically near intramuscular axons and NMJs. Interestingly, strong expression of activated glial markers, glial fibrillary acidic protein (GFAP) and nestin, was observed in the areas adjacent to NMJs. Finally, we determined whether ex vivo trophic factor delivery influences inflammation and terminal Schwann cell (TSC) response during ALS. We found that intramuscular transplantation of hMSC-GDNF tended to exhibit less inflammation and significantly maintained TSC association with NMJs. Understanding cellular responses near NMJs is important to identify suitable cellular and molecular targets for novel treatment of ALS and other neuromuscular diseases.
Databáze: OpenAIRE
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