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

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

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 3

Ly6Chi monocytes in the spleen exhibit a proinflammatory profile 2 months prior to clinical disease onset and during disease progression in SOD1 mice.

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Ly6Chi monocytes in the spleen exhibit a proinflammatory profile 2 month...
Quantitative nCounter expression profiling of 179 inflammation-related genes showing significantly (A) upregulated and (B) downregulated genes in splenic Ly6Chi monocytes compared with non-Tg littermates of the same mice analyzed in Figure 2 at presymptomatic (30 and 60 days of age), disease onset, and end stages. Data for A and B represent mean ± SD. All shown genes were significantly affected (P < 0.05). The complete list of P values for each significantly affected gene is shown in Supplemental Table 2. Gene expression level was normalized against the geometric mean of 6 housekeeping genes (Cltc, Gapdh, Gusb, Hprt1, Pgk1, Tubb5). (C) qRT-PCR analysis of Ahr mRNA expression in splenic Ly6C monocyte subsets sorted by flow cytometry from non-Tg, SOD1WT, and SOD1G93A mice at disease onset. Total RNA was isolated and pooled from 3–5 mice for each cell population. Expression levels were normalized to Gapdh. Data represent mean ± SEM. ***P < 0.001, Student’s t test (2-tailed). Results are representative of 2 independent experiments.