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Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Oleg Butovsky, … , Merit E. Cudkowicz, Howard L. Weiner
Oleg Butovsky, … , Merit E. Cudkowicz, Howard L. Weiner
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3063-3087. https://doi.org/10.1172/JCI62636.
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Research Article Neuroscience Article has an altmetric score of 29

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

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Abstract

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.

Authors

Oleg Butovsky, Shafiuddin Siddiqui, Galina Gabriely, Amanda J. Lanser, Ben Dake, Gopal Murugaiyan, Camille E. Doykan, Pauline M. Wu, Reddy R. Gali, Lakshmanan K. Iyer, Robert Lawson, James Berry, Anna M. Krichevsky, Merit E. Cudkowicz, Howard L. Weiner

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Figure 12

Anti-Ly6C mAb treatment delays disease onset and extends survival in SOD1 mice.

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Anti-Ly6C mAb treatment delays disease onset and extends survival in SOD...
SOD1G93A mice were treated i.p. with IgG2a (IC; 100 μg, n = 11) or 100 μg anti-6C3 mAb (n = 11) every other day starting at the onset of the disease. (A) Kaplan-Meier analysis of the probability of surviving of SOD1 as function of age. Mantel-Cox’s F-test comparison showed groups treated with 100 μg IC versus anti-Ly6C (P = 0.0097). (B) Time-to-event analysis for disease neurologic onset (neurological severity score of 2). Disease onset was significantly delayed (P = 0.0127) by anti-Ly6C (100 μg) treatment. (C) Rotarod performance of IC- and anti-Ly6C–treated groups as a function of age. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, IC compared with anti-Ly6C groups by factorial ANOVA and Fisher’s least significant difference post hoc test. (D) Weight loss plotted for IC- and anti-Ly6C–treated groups. Data represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, 2-way ANOVA, Bonferroni post hoc test. (E) Duration of an early disease phase (from onset to 5% weight loss) and a later disease phase (from 5% weight loss to end stage). Data represent mean ± SEM. *P < 0.05, ***P < 0.001, 1-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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