Chondroitin sulfate disaccharide stimulates microglia to adopt a novel regulatory phenotype

Ebert, Stefanie; Schoeberl, Tobias; Walczak, Yana; Stoecker, Katharina; Stempfl, Thomas; Moehle, Christoph; Weber, Bernhard H. F.; Langmann, Thomas

doi:10.1189/jlb.0208138

Cited by 41 publications

(25 citation statements)

References 25 publications

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“…661W is a retinoblastoma-derived cell line, which represents an established model to study microglial neurotoxicity in the special context of retinal degeneration [30,31,35]. 661W cells were incubated for 48 h with culture supernatants from unstimulated, curcumin-, LPS- or LPS + curcumin-treated BV-2 cells and 661W photoreceptor cell morphology was assessed by phase contrast microscopy.…”

Section: Resultsmentioning

confidence: 99%

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Curcumin is a potent modulator of microglial gene expression and migration

Karlstetter

Lippe

Walczak

et al. 2011

J Neuroinflammation

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112

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BackgroundMicroglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB) signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin.MethodsResting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium.ResultsCurcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and Signal transducer and activator of transcription 1 was reduced in LPS-triggered microglia. These transcriptional changes in curcumin-treated LPS-primed microglia also lead to decreased neurotoxicity with reduced apoptosis of 661W photoreceptor cultures.ConclusionsCollectively, our results suggest that curcumin is a potent modulator of the microglial transcriptome. Curcumin attenuates microglial migration and triggers a phenotype with anti-inflammatory and neuroprotective properties. Thus, curcumin could be a nutraceutical compound to develop immuno-modulatory and neuroprotective therapies for the treatment of various neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

“…MTT assays revealed that 100 ng/ml LPS, 20 μM curcumin, or a combination of both had no cytotoxic effects on BV-2 cells (data not shown). 661W photoreceptor-like cells were a gift from Prof. Muayyad Al-Ubaidi (University of Illinois, Chicago, IL) and the culture conditions have been described elsewhere [31]. …”

Section: Methodsmentioning

confidence: 99%

Curcumin is a potent modulator of microglial gene expression and migration

Karlstetter

Lippe

Walczak

et al. 2011

J Neuroinflammation

Self Cite

112

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“…Motor neuron injury occurs in amyotrophic lateral sclerosis through both cell autonomous-and noncell-autonomous pathways. Multiple mechanisms can lead to motor neuron injury, which funnel into a final pathway or noncell-autonomous toxicity and neuroinflammation leading to motor neuron death [59][60][61][62][63]. In contrast, M2 produce high levels of antiinflammatory cytokines and neurotrophic factors including IL-4, IL-10, and insulin-like growth factor (IGF)-1 in addition other neruoprotection signals such as CD200 and fractalkine [51,60,[64][65][66][67][68].…”

Section: Microgliamentioning

confidence: 99%

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

et al. 2015

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Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.

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“…Our laboratory has used large-scale transcriptional phenotyping to identify characteristic gene signatures of LPS and chondroitin sulfate proteoglycan-disaccharide (CSPG-DS) stimulated BV-2 microglia as clearly polarized cell populations (27). Moreover, we have profiled primary retinal microglia from wild-type (wt) and retinoschisin-deficient (Rs1h 2/Y ) mice (28), a prototypic model for rapid retinal apoptosis and degeneration (29).…”

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confidence: 99%