From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis

Lincecum, John; Vieira, Fernando; Wang, Monica Z.; Thompson, Kenneth; Zutter, Gerald S De; Kidd, Joshua D.; Moreno, Andrew; Sánchez, Ricardo Mondragón; Carrion, Isarelis J; Levine, Beth A.; Al‐Nakhala, Bashar M.; Sullivan, Shawn M; Gill, Alan; Perrin, Steven

doi:10.1038/ng.557

Cited by 106 publications

(85 citation statements)

References 39 publications

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“…There is also potential indication that NOX1 deficiency might slow the course of the ALS mouse model (118). One pharmacological study using the antioxidant/NOX inhibitor apocynin suggested a strong increase in the survival of ALS mice (68); however, this was not confirmed by other studies (110,170).…”

Section: Studies In Humansmentioning

confidence: 68%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

248

231

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Significance: There is increasing evidence that the generation of reactive oxygen species (ROS) in the central nervous system (CNS) involves the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Controlled ROS generation appears necessary for optimal functioning of the CNS through fine-tuning of redoxsensitive signaling pathways, while overshooting ROS generation will lead to oxidative stress and CNS disease. Recent Advances: NOX enzymes are not only restricted to microglia (i.e. brain phagocytes) but also expressed in neurons, astrocytes, and the neurovascular system. NOX enzymes are involved in CNS development, neural stem cell biology, and the function of mature neurons. While NOX2 appears to be a major source of pathological oxidative stress in the CNS, other NOX isoforms might also be of importance, for example, NOX4 in stroke. Globally speaking, there is now convincing evidence for a role of NOX enzymes in various neurodegenerative diseases, cerebrovascular diseases, and psychosis-related disorders. Critical Issues: The relative importance of specific ROS sources (e.g., NOX enzymes vs. mitochondria; NOX2 vs. NOX4) in different pathological processes needs further investigation. The absence of specific inhibitors limits the possibility to investigate specific therapeutic strategies. The uncritical use of non-specific inhibitors (e.g., apocynin, diphenylene iodonium) and poorly validated antibodies may lead to misleading conclusions. Future Directions: Physiological and pathophysiological studies with cell-type-specific knock-out mice will be necessary to delineate the precise functions of NOX enzymes and their implications in pathomechanisms. The development of CNS-permeant, specific NOX inhibitors will be necessary to advance toward therapeutic applications. Antioxid. Redox Signal. 20, 2815Signal. 20, -2837

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Section: Studies In Humansmentioning

confidence: 68%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

248

231

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“…Our investigations found perivascular and intraparenchymal CD4 + T lymphocytes in the proximity of degenerating corticospinal tracts and ventral horns in two-thirds of ALS patients (11). In the blood of patients with ALS, alterations in T lymphocyte populations have also been described as compared with controls (12)(13)(14)(15)(16); however, these studies do not address whether T lymphocytes directly or indirectly influence disease progression.…”

Section: Introductionmentioning

confidence: 74%

ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

Beers¹,

Zhao²,

Wang³

et al. 2017

JCI Insight

168

155

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“…Although ALS is not primarily considered an inflammatory or immune-mediated disease, immune mechanisms appear to play a role in pathogenesis of the disease. In both ALS patients and animal models, inflammatory responses are observed (2)(3)(4)(5)(6)(7)(8). Furthermore, non-neuronal cells such as microglia (9) and astrocytes (10) are activated during disease progression, and evidence suggests that they contribute to neuronal death.…”

Section: Introductionmentioning

confidence: 99%

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

Butovsky¹,

Siddiqui²,

Gabriely³

et al. 2012

J. Clin. Invest.

423

452

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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 Ly6C hi 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 Ly6C hi 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.

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From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis

Cited by 106 publications

References 39 publications

New Insights onNOXEnzymes in the Central Nervous System

New Insights onNOXEnzymes in the Central Nervous System

ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

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

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