Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis.

ABSTRACT: Tubule-interstitial nephritis (TIN) results in decreased renal function and interstitial inflammation, which ultimately leads to fibrosis. Excessive adenine intake can cause TIN because xanthine dehydrogenase (XDH) can convert this purine into an insoluble compound, which precipitates in the tubuli. Innate immune sensors, such as Toll-like receptors (TLR) and inflammasome complex, play a crucial role in the initiation of inflammation. The aim of this study was to evaluate the roles of TLR-2 and -4, Myd88 and inflammasome complex in an experimental model of TIN. Here, we show that wild-type (WT) mice fed adenine-enriched food exhibited significant renal dysfunction and enhanced cellular infiltration accompanied by collagen deposition. They also presented higher gene and protein expression of pro-inflammatory cytokines. In contrast, TLR-2, -4, MyD88, ASC and Caspase-1 KO mice showed renoprotection associated with expression of inflammatory molecules at levels comparable to controls. Furthermore, treatment of WT animals with allopurinol, an XDH inhibitor, led to reduced levels of uric acid, oxidative stress, collagen deposition and a downregulation of the NF-kB signaling pathway. We concluded that MyD88 signaling and inflammasome participate in the development of TIN. Furthermore, inhibition of XDH seems to be a promising way to therapeutically target the developing inflammatory process.

SUBMITTER: Correa-Costa M

PROVIDER: S-EPMC3237574 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: in vitro, ex vivo studies.

Project description:MyD88 is an adapter protein that links toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs) with downstream signaling molecules. The MyD88 has been found to be an essential mediator in the development of osteoarthritis in articular cartilage. However, the role of the MyD88 pathway has yet to be elucidated in the intervertebral disk (IVD). Using in vitro techniques, we analyzed the effect of MyD88 pathway-specific inhibition on the potent inflammatory and catabolic mediator LPS and IL-1 in bovine and human nucleus pulposus (NP) cells by assessing matrix-degrading enzyme expression, including matrix metalloproteases (MMPs) and a disintegrin-like and metalloprotease with thrombospondin motifs (ADAMTS family). We also analyzed inhibition of MyD88 in the regulation of inducible nitric oxide synthase and TLR-2. Finally, we used an ex vivo organ culture model to assess the effects of MyD88 inhibitor (MyD88i) on catabolic factor-induced disk degeneration in mice lumbar disks. In bovine NP cells, MyD88i potently antagonizes LPS- or IL-1-mediated induction of cartilage-degrading enzyme production, including MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5. MyD88i also attenuates the LPS- or IL-1-mediated induction of iNOS and TLR-2 gene expression. Our ex vivo findings reveal inhibition of MyD88 via counteraction of IL-1-mediated proteoglycan depletion. The findings from this study demonstrate the potent anti-inflammatory and anti-catabolic effects of inhibition of MyD88 pathway inhibition on IVD homeostasis, suggesting a potential therapeutic benefit of a MyD88i in degenerative disk disease in the future.

| S-EPMC3518428 | biostudies-literature

Oncogenic MyD88 Mutants Require Toll-like Receptors

Project description:In the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the most frequent gain-of-function mutations target MyD88, a signaling adapter for Tolllike receptors (TLRs). The most prevalent oncogenic mutant, MyD88 L265P, occurs in 29% of cases and is the most active in engaging the NF-kappaB pathway. Here we show that MyD88 mutants do not function autonomously, but rather require TLR7, TLR9, and to a lesser extent, TLR4 to promote the survival of ABC DLBCL cells. Unlike wild type MyD88, MyD88 mutants associate constitutively with TLR7 and TLR9 in ABC DLBCL cells. Like ligand-induced TLR7/9 signaling in normal immune cells, the survival of ABC DLBCL cell lines depends upon translocation of TLR7 and TLR9 to acidic endolysosomes, where proteolytic processing of their ligand binding ectodomains is required for their oncogenic signaling. ABC DLBCL viability also depends upon CD14, a co-receptor for TLR7 and TLR9 that promotes engagement of nucleic acid ligands by these receptors. Point mutations in the TLR7 or TLR9 ectodomains that abrogate ligand binding and/or signaling were incapable of sustaining ABC DLBCL survival. An inhibitory oligonucleotide that suppresses TLR9 responses in normal B cells blocked NF-kappaB signaling and survival of ABC DLBCL lines. Together, these data suggest that an endogenous TLR ligand may play a pathogenic role in ABC DLBCL and provide a rationale for targeting TLR signaling to improve therapy of this aggressive lymphoma.

2014-05-21 | GSE47147 | GEO

Toll-like receptors in lupus nephritis.

Project description:The pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) is based on the loss of self-tolerance against ubiquitous autoantigens involving all mechanisms of adaptive immunity. However, data accumulating over the last decade imply an important role also for numerous elements of innate immunity, namely the Toll-like receptors in the pathogenesis of SLE. Here we discuss their role in the most common organ complication of SLE, i.e. lupus nephritis. We summarize experimental and clinical data on the expression and functional contribution of the Toll-like receptors in immune complex glomerulonephritis, and intrarenal inflammation. Based on these discoveries Toll-like receptors are evolving as therapeutic targets for the treatment of SLE and lupus nephritis.

| S-EPMC5898010 | biostudies-literature

Oncogenic MyD88 Mutants Require Toll-like Receptors

2014-05-21 | E-GEOD-47147 | biostudies-arrayexpress

Toll-like receptors revisited; a possible role for TLR1 in lupus nephritis.

Project description: Not available

| S-EPMC7892377 | biostudies-literature

Targeting Toll-like receptors with small molecule agents.

Project description:Toll-like receptors (TLRs) are type I transmembrane proteins that are key regulators of both innate and adaptive immune responses. To protect the host from viral and bacterial threats, TLRs trigger a pro-inflammatory immune response by detecting pathogen and danger associated molecular patterns. Considerable evidence has accumulated to show that the dysregulation of TLR signaling contributes to the development and progression of numerous diseases. Therefore, TLRs are emerging as important drug discovery targets. Currently, there is great interest in the development of TLR small molecule modulators for interrogating TLR signaling and treating diseases caused by TLR signaling malfunctions. In this tutorial review, we will outline methods for the discovery of TLR small molecule modulators and the up-to-date progress in this field. Small molecules targeting TLRs not only provide an opportunity to identify promising drug candidates, but also unveil knowledge regarding TLR signaling pathways.

| S-EPMC3665707 | biostudies-literature

Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes.

Project description:MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N = 64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in CD34+ cells had a tendency for shorter survival compared to the ones with lower MYD88, which was significant when controlled for IPSS and age. We then evaluated effect of MYD88 blockade in the CD34+ cells of patients with lower-risk MDS. Colony formation assays indicated that MYD88 blockade using a MYD88 inhibitor resulted in increased erythroid colony formation. MYD88 blockade also negatively regulated the secretion of interleukin-8. Treatment of MDS CD34+ cells with an IL-8 antibody also increased formation of erythroid colonies. These results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.

| S-EPMC3744562 | biostudies-literature

Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits.

Project description:The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death.

| S-EPMC1959462 | biostudies-literature

Pantoprazole-induced acute interstitial nephritis.

Project description: Not available

| S-EPMC3537780 | biostudies-literature

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88.

Project description:Oil-in-water emulsions have been successfully used to increase the efficacy, immunogenicity, and cross-protection of human vaccines; however, their mechanism of action is still largely unknown. Nlrp3 inflammasome has been previously associated to the activity of alum, another adjuvant broadly used in human vaccines, and MyD88 adaptor protein is required for the adjuvanticity of most Toll-like receptor agonists. We compared the contribution of Nlrp3 and MyD88 to the adjuvanticity of alum, the oil-in-water emulsion MF59, and complete Freund's adjuvant in mice using a three-component vaccine against serogroup B Neisseria meningitidis (rMenB). Although the basal antibody responses to the nonadjuvanted rMenB vaccine were largely dependent on Nlrp3, the high-level antibody responses induced by alum, MF59, or complete Freund's adjuvant did not require Nlrp3. Surprisingly, we found that MF59 requires MyD88 to enhance bactericidal antibody responses to the rMenB vaccine. Because MF59 did not activate any of the Toll-like receptors in vitro, we propose that MF59 requires MyD88 for a Toll-like receptor-independent signaling pathway.

| S-EPMC3131326 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data