TLRs and chronic inflammation

Ospelt, Caroline; Gay, Steffen

doi:10.1016/j.biocel.2009.10.010

Cited by 162 publications

(136 citation statements)

References 163 publications

(147 reference statements)

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“…Dysregulation of TLR signaling pathways leads to increased expression of cytokines and chemokines, causing tissue damage and chronic inflammation (18). As a number of studies have shown, when TLRs are stimulated, there is a concomitant activation of inflammatory and anti-inflammatory pathways (28), the latter being needed to limit the inflammatory response and avoid tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…The amount and type of cytokines released after the TLR activation regulate the differentiation and functional state of dendritic cells and influence T cell activation and differentiation (17). Aberrant stimulation of TLRs or dysregulation of TLR signaling pathways results in increased expression of cytokines and chemokines, creating a vicious inflammatory cycle that contributes to the initiation and progression of chronic inflammatory diseases and autoimmune diseases such as rheumatoid arthritis (18,19).…”

mentioning

confidence: 99%

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Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Prencipe

Minnone

Strippoli

et al. 2014

The Journal of Immunology

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Nerve growth factor (NGF) levels are highly increased in inflamed tissues, but their role is unclear. We show that NGF is part of a regulatory loop in monocytes: inflammatory stimuli, while activating a proinflammatory response through TLRs, upregulate the expression of the NGF receptor TrkA. In turn, NGF, by binding to TrkA, interferes with TLR responses. In TLR-activated monocytes, NGF reduces inflammatory cytokine production (IL-1β, TNF-α, IL-6, and IL-8) while inducing the release of anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist). NGF binding to TrkA affects TLR signaling, favoring pathways that mediate inhibition of inflammatory responses: it increases Akt phosphorylation, inhibits glycogen synthase kinase 3 activity, reduces IκB phosphorylation and p65 NF-κB translocation, and increases nuclear p50 NF-κB binding activity. Use of TrkA inhibitors in TLR-activated monocytes abolishes the effects of NGF on the activation of anti-inflammatory signaling pathways, thus increasing NF-κB pathway activation and inflammatory cytokine production while reducing IL-10 production. PBMC and mononuclear cells obtained from the synovial fluid of patients with juvenile idiopathic arthritis show marked downregulation of TrkA expression. In ex vivo experiments, the addition of NGF to LPS-activated juvenile idiopathic arthritis to both mononuclear cells from synovial fluid and PBMC fails to reduce the production of IL-6 that, in contrast, is observed in healthy donors. This suggests that defective TrkA expression may facilitate proinflammatory mechanisms, contributing to chronic tissue inflammation and damage. In conclusion, this study identifies a novel regulatory mechanism of inflammatory responses through NGF and its receptor TrkA, for which abnormality may have pathogenic implications for chronic inflammatory diseases

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Prencipe

Minnone

Strippoli

et al. 2014

The Journal of Immunology

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“…The ligand of this complex is however not yet known. TLR1 is expressed in leukocytes and in non-immune cells such as astrocytes, fibroblasts, keratinocytes, endothelial and epithelial cells (Ospelt and Gay, 2008b). It was found to be expressed also by synovial fibroblasts, including RASF (Ospelt et al, 2008).…”

Section: Toll-like Receptors (Tlr) In Ramentioning

confidence: 99%

“…In individuals positive for HLA-DRβ smoking significantly increases the risk of developing RA (Klareskog et al, 2006). On the other hand smoking might induce ligands to trigger TLR signalling (Ospelt and Gay, 2008b). In conclusion, the latest research proving the involvement of the innate immune system into the pathogenesis of RA contributes to a better understanding of the initiation of the disease as well as might point to possible targets for novel therapies in RA.…”

Section: Shared Epitopes As Part Of Innate Immunitymentioning

confidence: 99%

“…Even though there has been recently accumulating evidence for the involvement of the innate immune system into the development of synovitis (Ospelt and Gay, 2008b), adaptive immunity has long been known to play a critical role in the pathogenesis of RA. In autoimmune disorders, such as RA, the cells of the adaptive immunity recognize self antigens and propagate a self directed autoimmune reaction.…”

Section: Autoimmunitymentioning

confidence: 99%

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Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis

Rodrigues

Jüngel

2009

Molecular Immunology

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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the progressive and irreversible destruction of joints.RA remains an incurable condition, although a new class of drugs, biologicals, have made a major breakthrough in targeting and/or eliminating the immune cells, including T cells, B cells and monocytes/macrophages from the joints. That we cannot (yet?) cure the disease is most likely due to the lack of therapeutic targeting the endogenously activated RA synovial fibroblasts (RASF).Most interestingly, RASF express Toll-like receptors 1-6 rendering them prone to activation by exogenous and endogenous TLR ligands and resulting in the production of numerous powerful chemokines and cytokines. These factors are responsible for the repopulation of immune cells in the joints after ceasing cell depleting therapies.To characterize the molecular mechanisms of synovial activation, a new approach studying the epigenetic characteristics of RASF has been recently undertaken.Thereby, the pattern of histone acetylation, DNA methylation and gene expression regulating microRNA are being explored.Since auto-antibodies have the most predictive and diagnostic value for RA, it is challenging to study more comprehensively the contribution of auto-antibodies to the disease. A new screening technique, serological analysis of recombinant human cDNA expression library (SEREX), adapted from cancer research allowed for the identification of novel auto-antibodies in RA, including anti-serpin E2 auto-antibodies.The serpin E2 auto-antibodies were found to inhibit the activity of serpin E2 and have potentially a functional role in the disease. The recent findings in the field of innate immunity, epigenetics and autoimmunity related to the pathogenesis of RA are in the scope of this review. 2

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TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

Yin

Shen

et al. 2017

The Anatomical Record

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Bacteria/virus-induced chronic inflammation is involved in both tumor initiation and tumor progression. Toll-like receptor 4 (TLR4) has been implicated in the development of several types of cancer. In this study, we explored the impact of TLR4 activation by lipopolysaccharide (LPS) on breast cancer metastasis and associated signaling molecules. We first examined TLR4 expression levels in breast tissue using a human breast tissue microarray and breast cell lines. We then studied the role of TLR4 activation by LPS stimulation in breast cancer metastasis using both in vitro and in vivo models. Finally, we investigated signaling molecules involved in the process using Western blotting and fluorescent immunohistochemistry staining. The results showed that TLR4 expression levels increased in breast cancer tissue compared to normal breast tissue. In addition, our results also showed that TLR4 pathway activation by LPS stimulation in MCF7 and MDA-MB-231 breast cancer cells caused the following actions: (1) promotes migration of breast cancer cells, (2) triggers the β-catenin signaling pathway via PI3K/Akt/GSK3β, and (3) promotes transcription of downstream β-catenin target genes leading to breast cancer metastasis. This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. The results suggest that the Akt/GSK3β/β-catenin signal transduction pathway may serve as a viable clinical treatment target in breast cancer. Anat Rec, 300:1219-1229, 2017. © 2017 Wiley Periodicals, Inc.

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TLRs and chronic inflammation

Cited by 162 publications

References 163 publications

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

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