Search results for "TLR"

2020

Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naive T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent …

Evolutionary redesign of the Atlantic cod (Gadus morhua L.) Toll-like receptor repertoire by gene losses and expansions

2016

AbstractGenome sequencing of the teleost Atlantic cod demonstrated loss of the Major Histocompatibility Complex (MHC) class II, an extreme gene expansion of MHC class I and gene expansions and losses in the innate pattern recognition receptor (PRR) family of Toll-like receptors (TLR). In a comparative genomic setting, using an improved version of the genome, we characterize PRRs in Atlantic cod with emphasis on TLRs demonstrating the loss of TLR1/6, TLR2 and TLR5 and expansion of TLR7, TLR8, TLR9, TLR22 and TLR25. We find that Atlantic cod TLR expansions are strongly influenced by diversifying selection likely to increase the detectable ligand repertoire through neo- and subfunctionalizatio…

Nitration of Wheat Amylase Trypsin Inhibitors Increases Their Innate and Adaptive Immunostimulatory Potential

2018

Amylase trypsin inhibitors (ATI) can be found in all gluten containing cereals and are, therefore, ingredient of basic foods like bread or pasta. In the gut ATI can mediate innate immunity via activation of the Toll-like receptor 4 (TLR4) on immune cells residing in the lamina propria, promoting intestinal, as well as extra-intestinal, inflammation. Inflammatory conditions can induce formation of peroxynitrite (ONOO-) and, thereby, endogenous protein nitration in the body. Moreover, air pollutants like ozone (O3) and nitrogen dioxide (NO2) can cause exogenous protein nitration in the environment. Both reaction pathways may lead to the nitration of ATI. To investigate if and how nitration mo…

Intravenous delivery of the toll-like receptor 7 agonist SC1 confers tumor control by inducing a CD8+ T cell response

2019

TLR7 agonists are considered promising drugs for cancer therapy. The currently available compounds are not well tolerated when administered intravenously and therefore are restricted to disease settings amenable for topical application. Here we present the preclinical characterization of SC1, a novel synthetic agonist with exquisite specificity for TLR7. We found that intravenously administered SC1 mediates systemic release of type I interferon, but not of proinflammatory cytokines such as TNFα and IL6, and results in activation of circulating immune cells. Tumors of SC1-treated mice have brisk immune cell infiltrates and are polarized towards a Th1 type signature. Intratumoral CD8(+) T cel…

RNA Modifications Modulate Activation of Innate Toll-Like Receptors

2019

Self/foreign discrimination by the innate immune system depends on receptors that identify molecular patterns as associated to pathogens. Among others, this group includes endosomal Toll-like receptors, among which Toll-like receptors (TLR) 3, 7, 8, and 13 recognize and discriminate mammalian from microbial, potentially pathogen-associated, RNA. One of the discriminatory principles is the recognition of endogenous RNA modifications. Previous work has identified a couple of RNA modifications that impede activation of TLR signaling when incorporated in synthetic RNA molecules. Of note, work that is more recent has now shown that RNA modifications in their naturally occurring context can have …

TLR2 modulates gut colonization and dissemination of Candida albicans in a murine model

2016

Invasive candidiasis often arises from translocation of endogenous yeasts from the gastrointestinal tract to the bloodstream. Here we describe that both wild type and TLR2−/− mice strains, orally administered with Candida albicans yeasts, display similar sustained high level of gut colonization when oral antibacterial treatment is present, while removal of antibiotic treatment causes a progressive clearance of yeasts in control but not in TLR2−/− mice. Fungal invasion of internal organs, following immunosuppression of colonized mice, was increased in TLR2−/− mice. These results point out to a role of TLR2 in gut protection against colonization and endogenous invasion by C. albicans. This wo…

The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin A nephropathy and a…

2021

  The proteasome to immunoproteasome (iPS) switch consists of β1, β2 and β5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VAL…

Filifactor alocis and Tumor Necrosis Factor-Alpha Stimulate Synthesis of Visfatin by Human Macrophages

2021

There is little known about the effect of the periodontopathogen Filifactor alocis on macrophages as key cells of the innate immune defense in the periodontium. Therefore, the aim of the present study was to investigate the effect of F. alocis and additionally of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF&alpha

PRR signaling during in vitro macrophage differentiation from progenitors modulates their subsequent response to inflammatory stimuli.

2017

Toll-like receptor (TLR) agonists drive hematopoietic stem and progenitor cells (HSPCs) to differentiate along the myeloid lineage in vitro and also in vivo following infection. In this study, we used an in vitro model of HSPC differentiation to investigate the functional consequences (cytokine production) that exposing HSPCs to various pathogen-associated molecular patterns (PAMPs) and Candida albicans cells have on the subsequently derived macrophages. Mouse HSPCs (Lin- cells) were cultured with GM-CSF to induce macrophage differentiation in the presence or absence of the following pattern recognition receptor (PRR) agonists: Pam3CSK4 (TLR2 ligand), LPS (TLR4 ligand), depleted zymosan (wh…

Immunosuppression, peripheral inflammation and invasive infection from endogenous gut microbiota activate retinal microglia in mouse models

2016

Although its actual role in the progression of degenerative processes is not fully known, the persistent activated state of retinal microglia and the concurrent secretion of inflammatory mediators may contribute to neuronal death and permanent vision loss. Our objective was to determine whether non-ocular conditions (immunosuppression and peripheral inflammation) could lead to activation of retinal microglia. Mouse models of immunosuppression induced by cyclophosphamide and/or peripheral inflammation by chemically induced sublethal colitis in C57BL/6J mice were used. Retinal microglia morphology, spatial distribution and complexity, as well as MHCII and CD11b expression levels were determin…