Impaired activation of ALS monocytes by exosomes

Zondler, Lisa; Feiler, Marisa S.; Freischmidt, Axel; Ruf, Wolfgang; Ludolph, Albert C.; Danzer, Karin M; Weishaupt, Jochen H.

doi:10.1038/icb.2016.89

Cited by 40 publications

(38 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have reported the activation of monocytes in the peripheral blood of ALS patients ( 100 ), as well as the increased invasion of peripheral monocytes into the spinal cord of ALS patients and mice ( 101 , 102 ), which contributed to MN loss. Activated monocytes from ALS patients exhibited decelerated phagocytosis, altered adhesion behavior, and impaired proinflammatory cytokine secretion ( 102 , 103 ). A recent study revealed 233 differentially expressed genes in ALS monocytes.…”

Section: Neuroinflammation In Als: Perspective On Cellular Basismentioning

confidence: 99%

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

2017

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.

show abstract

Section: Neuroinflammation In Als: Perspective On Cellular Basismentioning

confidence: 99%

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

2017

View full text Add to dashboard Cite

show abstract

“…Another study found that there was increased expression of HLA-DR on CD14 + monocytes in ALS and this correlated with the rate of disease progression (58). Another study used exosomes to activate monocytes, and found that monocytes from ALS patients were less responsive than those from healthy individuals (109). ALS monocytes are less responsive to purinergic stimulation than those from controls (110).…”

Section: Monocyte Numbers and Proportionsmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

show abstract

“…This fatal and progressive neurodegenerative disease affects motor neurons (MNs) in the spinal cord and motor cortex. However, neuroinflammation and peripheral immune system activation were shown to accompany ALS neurodegeneration (Zondler et al, 2017). The underlying mechanisms are still unknown, but seem to involve multiple neural cell dysfunctional processes and complex multisystem deregulation, what turns difficult the identification of specific targets and the development of successful therapies.…”

Section: Introductionmentioning

confidence: 99%

Exosomes from NSC-34 Cells Transfected with hSOD1-G93A Are Enriched in miR-124 and Drive Alterations in Microglia Phenotype

et al. 2017

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder affecting motor neurons (MNs). Evidences indicate that ALS is a non-cell autonomous disease in which glial cells participate in both disease onset and progression. Exosomal transfer of mutant copper-zinc superoxide dismutase 1 (mSOD1) from cell-to-cell was suggested to contribute to disease dissemination. Data from our group and others showed that exosomes from activated cells contain inflammatory-related microRNAs (inflamma-miRNAs) that recapitulate the donor cell. While glia-derived exosomes and their effects in neurons have been addressed by several studies, only a few investigated the influence of motor neuron (MN)-derived exosomes in other cell function, the aim of the present study. We assessed a set of inflamma-miRs in NSC-34 MN-like cells transfected with mutant SOD1(G93A) and extended the study into their derived exosomes (mSOD1 exosomes). Then, the effects produced by mSOD1 exosomes in the activation and polarization of the recipient N9 microglial cells were investigated. Exosomes in coculture with N9 microglia and NSC-34 cells [either transfected with either wild-type (wt) human SOD1 or mutant SOD1(G93A)] showed to be transferred into N9 cells. Increased miR-124 expression was found in mSOD1 NSC-34 cells and in their derived exosomes. Incubation of mSOD1 exosomes with N9 cells determined a sustained 50% reduction in the cell phagocytic ability. It also caused a persistent NF-kB activation and an acute generation of NO, MMP-2, and MMP-9 activation, as well as upregulation of IL-1β, TNF-α, MHC-II, and iNOS gene expression, suggestive of induced M1 polarization. Marked elevation of IL-10, Arginase 1, TREM2, RAGE, and TLR4 mRNA levels, together with increased miR-124, miR-146a, and miR-155, at 24 h incubation, suggest the switch to mixed M1 and M2 subpopulations in the exosome-treated N9 microglial cells. Exosomes from mSOD1 NSC-34 MNs also enhanced the number of senescent-like positive N9 cells. Data suggest that miR-124 is translocated from the mSOD1 MNs to exosomes, which determine early and late phenotypic alterations in the recipient N9-microglial cells. In conclusion, modulation of the inflammatory-associated miR-124, in mSOD1 NSC-34 MNs, with potential benefits in the cargo of their exosomes may reveal a promising therapeutic strategy in halting microglia activation and associated effects in MN degeneration.

show abstract

Impaired activation of ALS monocytes by exosomes

Cited by 40 publications

References 35 publications

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

Exosomes from NSC-34 Cells Transfected with hSOD1-G93A Are Enriched in miR-124 and Drive Alterations in Microglia Phenotype

Contact Info

Product

Resources

About