Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progress...

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Bibliographic Details
Published in:The Journal of clinical investigation 2012-09, Vol.122 (9), p.3063-3087
Main Authors: Butovsky, Oleg, Siddiqui, Shafiuddin, Gabriely, Galina, Lanser, Amanda J, Dake, Ben, Murugaiyan, Gopal, Doykan, Camille E, Wu, Pauline M, Gali, Reddy R, Iyer, Lakshmanan K, Lawson, Robert, Berry, James, Krichevsky, Anna M, Cudkowicz, Merit E, Weiner, Howard L
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - drug therapy
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - immunology
Amyotrophic Lateral Sclerosis - pathology
Animals
Antibodies, Monoclonal - administration & dosage
Antigens, CD - genetics
Antigens, CD - metabolism
Antigens, Ly - genetics
Antigens, Ly - immunology
Antigens, Ly - metabolism
Apoptosis
Apyrase - genetics
Apyrase - metabolism
Biomedical research
Bone marrow
Brain
Care and treatment
Cell Proliferation
Chemotaxis
Development and progression
Disease
Female
Flow cytometry
Gene expression
Gene Regulatory Networks
Genes
Genetic aspects
Humans
Immunomodulation
Inflammation Mediators - metabolism
Investigations
Lymphocytes
Macrophages, Alveolar - metabolism
Male
Metabolic Networks and Pathways
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microglia - immunology
Microglia - pathology
MicroRNA
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
Monocytes
Monocytes - immunology
Monocytes - metabolism
Monocytes - pathology
Oligonucleotide Array Sequence Analysis
Pathogenesis
Properties
Rats
Rats, Inbred Lew
Recruitment
RNA Interference
Spinal cord
Spinal Cord - immunology
Spinal Cord - pathology
Spleen - immunology
Spleen - pathology
Superoxide Dismutase - genetics
Superoxide Dismutase-1
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptome
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Summary:Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI62636