Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

Kim, Sarah; Becker, Jéssica; Bechheim, Matthias; Kaiser, Vera B.; Noursadeghi, Mahdad; Fricker, Nadine; Beier, Esther; Klaschik, Sven; Boor, Peter; Hess, Timo; Hofmann, Andrea; Holdenrieder, Stefan; Wendland, Jens R.; Fröhlich, Holger; Hartmann, Gunther; Nöthen, Markus M.; Müller‐Myhsok, Bertram; Pütz, Benno; Hornung, Veit; Schumacher, Johannes

doi:10.1038/ncomms6236

Cited by 67 publications

(64 citation statements)

References 35 publications

(37 reference statements)

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“…Alterations in TLR4 and TLR2 expression as well as functional single nucleotide polymorphism (SNP) in genes expressed upon TLR4 activation have also been reported to be associated with CD [31,61] . As explained above, TLRs recognize bacterial or endogenous molecular patterns that, upon binding, trigger signal transduction via different adaptor molecules (MyD88 and TRIF) to induce proinflammatory gene expression.…”

Section: Strength Of Evidencementioning

confidence: 99%

“…As explained above, TLRs recognize bacterial or endogenous molecular patterns that, upon binding, trigger signal transduction via different adaptor molecules (MyD88 and TRIF) to induce proinflammatory gene expression. These play a vital role in host defense, but dysregulation in TLR signaling can also confer risk to autoimmune diseases, such as CD [61] . It is known that gut microbes provide signals that can both promote and inhibit autoimmunity by signaling through the TLR family [62] .…”

Section: Strength Of Evidencementioning

confidence: 99%

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Microbiome and Gluten

Sanz¹

2015

Ann Nutr Metab

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Celiac disease (CD) is a frequent chronic inflammatory enteropathy caused by gluten in genetically predisposed individuals that carry disease susceptibility genes (HLA-DQ2/8). These genes are present in about 30-40% of the general population, but only a small percentage of carriers develops CD. Gluten is the key environmental trigger of CD, but its intake does not fully explain disease onset; indeed, an increased number of cases experience gluten intolerance in late adulthood after many years of gluten exposure. Consequently, additional environmental factors seem to be involved in CD. Epidemiological studies indicate that common perinatal and early postnatal factors influence both CD risk and intestinal microbiota structure. Prospective studies in healthy infants at risk of developing CD also reveal that the HLA-DQ genotype, in conjunction with other environmental factors, influences the microbiota composition. Furthermore, CD patients have imbalances in the intestinal microbiota (dysbiosis), which are not fully normalized despite their adherence to a gluten-free diet. Therefore, it is hypothesized that the disease can promote dysbiosis that aggravates CD pathogenesis, and dysbiosis, in turn, can initiate and sustain inflammation through the expansion of proinflammatory pathobionts and decline of anti-inflammatory mutualistic bacteria. Studies in experimental models are also contributing to understand the role of intestinal bacteria and its interactions with a predisposed genotype in promoting CD. Advances in this area could aid in the development of microbiome-informed intervention strategies that optimize the partnership between the gut microbiota and host immunity for improving CD management.

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Section: Strength Of Evidencementioning

confidence: 99%

Section: Strength Of Evidencementioning

confidence: 99%

Microbiome and Gluten

Sanz¹

2015

Ann Nutr Metab

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“…An increasingly popular approach to identify genetic factors affecting interindividual variation in immune response is mapping expression quantitative trait loci (eQTLs) -variants that associate to gene expression -and to identify so-called response eQTLs (reQTLs) where the eQTL effect differs between immune stimuli [1][2][3][4][5][6] .…”

Section: Main Textmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMC) were obtained by Ficoll-Hypaque density gradient centrifugation of heparinized blood. Monocytes were isolated by MACS using CD14-microbeads (Miltenyi Biotec) as previously described 1 . The purity of isolated monocytes was ≥ 95%.…”

Section: Sample Collection Isolation and Stimulation Of Cd14+ Monocytesmentioning

confidence: 99%

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Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

Kim-Hellmuth

Bechheim

Puetz

et al. 2017

Preprint

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The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. We isolated monocytes from 134 genotyped individuals, stimulated the cells with three defined microbe-associated molecular patterns (LPS, MDP, and pppdsRNA), and profiled the transcriptome at three time points. After mapping expression quantitative trait loci (eQTL), we identified 417 response eQTLs (reQTLs) with differing effect between the conditions. We characterized the dynamics of genetic regulation on early and late immune response, and observed an enrichment of reQTLs in distal cis-regulatory elements. Response eQTLs are also enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover novel reQTL effects in multiple GWAS loci, and show a stronger enrichment of response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli modifying genetic predisposition to disease. Main TextAn increasingly popular approach to identify genetic factors affecting interindividual variation in immune response is mapping expression quantitative trait loci (eQTLs) -variants that associate to gene expression -and to identify so-called response eQTLs (reQTLs) where the eQTL effect differs between immune stimuli [1][2][3][4][5][6] .Such genetic variants can impact the transcriptional response to infection, and also represent genetic effects that are modified by the infectious environment via gene-byenvironment interactions. In this study, we create a data set of a large number of . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/116376 doi: bioRxiv preprint first posted online Mar. 13, 2017; -3 -immune stimulus conditions, with monocytes activated with microbial ligands for three different pattern recognition receptor (PRR) families at two different time points, next to the baseline condition.To examine the time course of innate immune responses, we first profiled gene expression in monocytes of five individuals using Human HT-12 v4 Expression BeadChips (Illumina) at six time points after stimulation with three prototypical microbial ligands: Lipopolysaccharide (LPS) was used to activate TLR4, muramyl-dipeptide (MDP) to stimulate NOD2, and 5'-triphosphate RNA (RNA) to activate RIG-I. Hierarchical clustering revealed early differentially expressed (DE) genes at 45 and 90 minutes after stimulation and late DE genes between 3 and 24 hours ( Supplementary Fig. 1). For the full eQTL cohort, we analyzed primary monocytes isolated from 134 healthy male individuals (185 before quality control), which were either untreated (baseline) or stimulated with the same three pathogenderived stimuli, and gene expression was profiled after 90 ...

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The role of toll‐like receptor 4 (TLR4) in cancer progression: A possible therapeutic target?

Kashani

Zandi

Pourbagheri‐Sigaroodi

et al. 2020

Journal Cellular Physiology

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The toll-like receptor (TLR) family consists of vital receptors responsible for pattern recognition in innate immunity, making them the core proteins involved in pathogen detection and eliciting immune responses. The most studied member of this family, TLR4, has been the center of attention regarding its contributory role in many inflammatory diseases including sepsis shock and asthma. Notably, mounting pieces of evidence have proved that this receptor is aberrantly expressed on the tumor cells and the tumor microenvironment in a wide range of cancer types and it is highly associated with the initiation of tumorigenesis as well as tumor progression and drug resistance. Cancer therapy using TLR4 inhibitors has recently drawn scientists' attention, and the promising results of such studies may pave the way for more investigation in the foreseeable future. This review will introduce the key proteins of the TLR4 pathway and how they interact with major growth factors in the tumor microenvironment. Moreover, we will discuss the many aspects of tumor progression affected by the activation of this receptor and provide an overview of the recent therapeutic approaches using various TLR4 antagonists.

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Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

Cited by 67 publications

References 35 publications

Microbiome and Gluten

Microbiome and Gluten

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

The role of toll‐like receptor 4 (TLR4) in cancer progression: A possible therapeutic target?

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