α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR

Costello, Derek A.; Carney, Dónal G.; Lynch, Marina A.

doi:10.1016/j.bbi.2015.01.005

Cited by 35 publications

(32 citation statements)

References 55 publications

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“…TLR2/3 deficiency attenuated the Aβ-induced changes in microglia. Consistently, our data have indicated that Aβ-induced increase in production of inflammatory cytokines was inhibited by pre-treating microglia with an anti-TLR2 antibody [16] and, interestingly, anti-TLR2 antibody prevented the Aβ-induced decrease in long-term potentiation (LTP), correlating with the evidence that the interaction of Aβ with TLR2 is associated with impaired cognition [14]. The evidence also indicates that administration of anti-TLR2 antibody to APP/PS1 mice improves cognitive function and this is associated with a decrease in microglial activation and with a decrease in Aβ accumulation, suggesting that it may affect phagocytosis [17].…”

Section: Introductionsupporting

confidence: 73%

“…Without the two signals, activation will not occur and therefore inhibiting one of the signals should prevent inflammasome activation. Since Aβ interacts to induce at least some of its actions by engaging TLR2, as confirmed by the finding that anti-TLR2 antibody inhibits Aβ-induced changes [16, 17], we argued that anti-TLR2 antibody would therefore inhibit the inflammasome and downstream changes.…”

Section: Introductionsupporting

confidence: 54%

“…Microglia were prepared as previously described [16]. Briefly, isolated mixed glia from cortical tissue of neonatal mice were cultured in T25 cm 2 flasks in Dulbecco’s modified Eagle’s medium (cDMEM) containing foetal bovine serum (FBS), penicillin and streptomycin (100 U/ml) supplemented with macrophage colony stimulating factor (M-CSF; 100 ng/ml; R&D Systems, UK) and granulocyte macrophage colony stimulating factor (GM-CSF; 100 ng/mL; R&D Systems, UK) for 10–12 days, after which time non-adherent microglia were seeded in 24-well plates (1 × 10 5 cells/well) and cultured for a further 2 days.…”

Section: Methodsmentioning

confidence: 99%

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Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Rubio-Araiz

Finucane

Keogh

et al. 2018

J Neuroinflammation

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BackgroundMicroglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-β (Aβ) in Alzheimer’s disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD.MethodsHere, we investigated whether an antibody that targets toll-like receptor (TLR)2 might attenuate the inflammatory and metabolic changes induced by lipopolysaccharide (LPS) and amyloid-β. The impact on phagocytosis was assessed by immunohistochemistry. We evaluated the metabolic changes with the SeaHorse Extracellular Flux Analyser and studied the expression of key enzymes driving glycolysis by western blotting. For all experiments, statistical significance was determined by unpaired Student’s t test and two-way analysis of variance (ANOVA).ResultsWe have reported that, when exposed to an inflammatory stimulus, microglia switch their metabolism towards the metabolically- inefficient glycolysis; this potentially impacts on metabolically demanding functions like phagocytosis. Anti-TLR2 antibody increased phagocytosis of Aβ in LPS + Aβ-stimulated microglia and this was linked with the ability of the antibody to attenuate the LPS + Aβ-triggered inflammasome activation. LPS + Aβ increased glycolysis in microglia and increased the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3, an enzyme that plays a key role in driving glycolysis; these effects were inhibited when cells were incubated with the anti-TLR2 antibody. The data also show that antibody treatment increased oxidative metabolism.ConclusionsThus, microglia with an inflammatory phenotype, specifically cells in which the inflammasome is activated, are glycolytic; this may compromise the metabolic efficiency of microglia and thereby provide an explanation for the reduced phagocytic function of the cells. We propose that, by restoring oxidative metabolism and reducing inflammasome activation in microglia, phagocytic function is also restored.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1281-7) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 73%

Section: Introductionsupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

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Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Rubio-Araiz

Finucane

Keogh

et al. 2018

J Neuroinflammation

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“…TLR signaling via the adaptor protein MyD88 mediates inflammatory responses, such as inducing microglial phagocytic activity in early stages of inflammation and increasing transcription of genes encoding IL-1 family cytokines (44,45). Indeed, inhibition of TLR2 or TLR4 reduces Aβ-stimulated microglial production of IL-1β and IL-6 (46,47). IL-33/ST2 signaling acts as a negative regulator of TLR signaling by competing with MyD88 (48,49).…”

Section: Discussionmentioning

confidence: 99%

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

Hung

Yuen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

295

285

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Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.innate immunity | synaptic plasticity | β-amyloid | microglia | neuroninflammation

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“…Microglia were prepared from neonatal C57/BL6 mice as previously described (Costello et al, 2015). Microglia (4x10 4 cells/cm 2 were plated onto coverslips coated with poly-D-lysine (5µg/ml; Merck Millipore Ltd, UK) and, after 48h, were preincubated with LPS (1µg/ml; Enzo Life Sciences, UK).…”

Section: Preparation Of Primary Glial Culturesmentioning

confidence: 99%

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice

Dempsey

Rubio-Araiz

Bryson

et al. 2017

Brain, Behavior, and Immunity

432

284

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., Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice, Brain, Behavior, and Immunity (2016), doi: http://dx.doi.org/10. 1016/j.bbi.2016.12.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impacts on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.

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α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR

Cited by 35 publications

References 55 publications

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice

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