Microglia are required for astroglial toll‐like receptor 4 response and for optimal TLR2 and TLR3 response

Holm, Thomas Hellesøe; Dræby, Dina; Owens, Trevor

doi:10.1002/glia.22296

Cited by 114 publications

(109 citation statements)

References 50 publications

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“…Despite low accessibility of exo-or endogen- reported that TLR4 is barely expressed and was incapable of mediating cellular activation in human astrocytes (7,8,16,17). In contrast, other data have shown that human astrocytes respond to LPS challenge (6,18,19), suggesting that human astrocytes may possess functional TLR4-LPS receptor complex and participate in innate immune response by signaling through interaction between TLR4 and its ligand,…”

Section: Introductionmentioning

confidence: 99%

LPS Sensing Mechanism of Human Astrocytes: Evidence of Functional TLR4 Expression and Requirement of Soluble CD14

et al. 2017

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Among a myriad of pathogen-associated molecular pattern-sensing receptors, toll-like receptors (TLRs) are the principal core sensors of the host. Despite intensive studies for the expression of TLRs and their roles in the central nervous system, controversies remain regarding the expression and the function of TLR4 in human astrocytes. In order to clarify this issue, we attempted to verify functional expression of TLR4 in human astrocytes. Using Reverse transcription-polymerase chain reaction (RT-PCR), we confirmed that the human astrocytes express the TLR4 constitutively. To determine the function of TLR4, astrocytes were treated with TLR4 ligand or lipopolysaccharide (LPS), and then inflammatory cytokines expressions were checked using RT-PCR and enzyme-linked immunosorbent assay. Nuclear factor (NF)-κB activation was checked using electrophoretic mobility shift assay. Treatment of astrocytes with LPS increased tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 expression and induced NF-κB activation. Neutralizing anti-TLR4 antibody blocked the effect of LPS on cytokine production and NF-κB activation in astrocytes. The effect of LPS on cytokine production and NF-κB activation was shown in the presence of serum but not in the absence of serum. Therefore, we investigated the sensing mechanism of LPS in human astrocytes. Human astrocytes were treated with LPS following neutralizing anti-CD14 antibody treatment in the presence of serum. Neutralizing anti-CD14 antibody treatment abolished the effect of LPS on cytokine expression and NF-κB activation. Additionally, supplement of recombinant CD14 in serum-free media induced LPS effect on cytokine production and NF-κB activation. In these results, we showed that human astrocytes constitutively express functional TLR4 and require soluble CD14 to recognize LPS.

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Section: Introductionmentioning

confidence: 99%

LPS Sensing Mechanism of Human Astrocytes: Evidence of Functional TLR4 Expression and Requirement of Soluble CD14

et al. 2017

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“…Glial cells, e.g., astrocytes and microglia, are key regulators of the innate immune response in the CNS. These cells are the primary responders to cellular stress and infection, which cause them to induce, produce, and release molecular signals that initiate glial responses, leading to inflammation, neurodegeneration, and apoptosis (4). Microglia cells are classified as specialized macrophages of the CNS because they release proinflammatory cytokines and chemokines.…”

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confidence: 99%

Expression and Function of Psoriasin (S100A7) and Koebnerisin (S100A15) in the Brain

et al. 2013

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The expression and function of psoriasin in the brain have been insufficiently characterized. Here, we show the induction of psoriasin expression in the central nervous system (CNS) after bacterial and viral stimulation. We used a pneumococcal meningitis in vivo model that revealed S100A15 expression in astrocytes and meningeal cells. These results were confirmed by a cell-based in vivo assay using primary rat glial and meningeal cell cultures. We investigated psoriasin expression in glial and meningeal cells using polyinosinic-polycytidylic acid, a synthetic analog of double-stranded RNA that mimics viral infection. Furthermore, previous results showed that antimicrobial peptides have not only bactericidal but also immunomodulatory functions. To test this statement, we used recombinant psoriasin as a stimulus. Glial and meningeal cells were treated with recombinant psoriasin at concentrations from 25 to 500 ng/ml. Treated microglia and meningeal cells showed phosphorylation of the extracellular signal-regulated kinase 1 (ERK1)/ERK2 (ERK1/2) signal transduction pathway. We demonstrated that this activation of ERK depends on RAGE, the receptor for advanced glycation end products. Furthermore, microglia cells treated with recombinant psoriasin change their phenotype to an enlarged shape. In conclusion, our results indicate an occurrence of psoriasin in the brain. An involvement of psoriasin as an antimicrobial protein that modulates the innate immune system after bacterial or viral stimulation is possible.

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“…They found that the CD4/CD8 lymphocyte ratio in vitreous is higher compared to the blood ratio in these PDR patients, demonstrating the presence of a local inflammatory process [7]. Prolonged local inflammation in hyperglycemic conditions in the retina may develop into a chronic inflammatory response that is detrimental to the integrity of BRB [6,[8][9][10]. The destruction of the barrier shifts the retina from its "privileged state" when the BRB functions normally to "compromised state" when the BRB has broken down.…”

Section: The Immune System In Proliferative Diabetic Retinopathymentioning

confidence: 93%

“…Their role in the pathogenesis of PDR is still under investigation but evidence suggests the possibility of a rather direct contribution. IL-6 controls immune cells responses by shifting T-helper cell populations, inhibiting the production of Th1 cells, promoting the differentiation of Th2 and Th17 cells, and infiltration of monocytes and T cells [9,10,83].…”

Section: Interleukinmentioning

confidence: 99%

Proliferative Diabetic Retinopathy: An Overview of Vitreous Immune and Biomarkers

Victor¹,

Sitompul²

2018

Early Events in Diabetic Retinopathy and Intervention Strategies

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This chapter discusses about the effect of vitreous immune system and biomarkers on the progression of proliferative diabetic retinopathy. Immune system and biomarkers have been believed to have an important role in the progression of diabetic retinopathy (DR) severity. Hyperglycemic will influence immune cells resulting in chronic inflammation on the retina. This condition progressively disrupts the blood-retinal barrier in retina causing those inflammatory molecules and immune cells to transfer from circulation. The transfer of these molecules plays an important part in the progression of proliferative diabetic retinopathy. In addition, biomarkers are indicators for some complex processes happened in our body, and are measured to determine diagnosis and prognosis of some treatment. There are several biomarkers that have been identified in DR patients including biomarkers of oxidative stress, hypoxia-inducible factors, angiogenic factors, pro-inflammatory cytokines, chemokines, cell adhesion molecules, and soluble CD200. The value of these biomarkers will tell us their possible role in the progression of DR. By improving the knowledge of molecular pathway in DR pathophysiology, the advancement of selective therapy approaches could be discovered and the management of DR could be more efficient.

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Microglia are required for astroglial toll‐like receptor 4 response and for optimal TLR2 and TLR3 response

Cited by 114 publications

References 50 publications

LPS Sensing Mechanism of Human Astrocytes: Evidence of Functional TLR4 Expression and Requirement of Soluble CD14

LPS Sensing Mechanism of Human Astrocytes: Evidence of Functional TLR4 Expression and Requirement of Soluble CD14

Expression and Function of Psoriasin (S100A7) and Koebnerisin (S100A15) in the Brain

Proliferative Diabetic Retinopathy: An Overview of Vitreous Immune and Biomarkers

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