Dataset Information

Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings.

ABSTRACT: The female reproductive tract (FRT) is the main site of entry of sexually transmitted infections (STIs). Toll-like receptors (TLRs) that recognize pathogenic motifs are widely expressed in the FRT. TLR stimulation induces immune activation and local production of inflammatory mediators. In the FRT, this response should also be compatible with reproductive functions and symbiosis with host microbiota. With a view to develop efficient mucosal vaccines to prevent STI acquisition, the role of TLR ligands in the FRT needs to be explored. We have therefore investigated the cytokine profiles of the different compartments of the FRT (vagina, endocervix, ectocervix, and uterus) before and after stimulation of mononuclear cells from human tissue specimens. The comparison with PBMCs allowed us to highlight the FRT specificities. We first characterized the main immune cell populations in each compartment and observed that their distribution was different through the compartments. The CD45+ cells represented a maximum of 11% in the FRT in contrast to 96% in PBMCs. We identified two main populations among the CD45+ cells in the four compartments of the FRT: CD3+ T cells (CD4+ and CD8+) and CD14+ APCs. B cell populations (CD19+) were much less frequent than T cells in all the FRT regions and were equally distributed. NK CD56+ cells were detected in all compartments and were more abundant in the uterus. Stimulation of the mononuclear cells was then performed with TLR agonists: R848 for TLR7/8, Poly I:C for TLR3, LPS for TLR4 and ODN CpG for TLR9. Cytokine levels in unstimulated cultures of cells isolated from all FRT compartments were higher than in cultures of unstimulated PBMCs. In contrast, after stimulation with TLR agonists, cytokine responses induced by TLR agonists were moderate in the FRT and significantly lower than in PBMCs. These responses were varied with different TLR ligands and FRT compartments. The cytokine profile induced by TLR activation in the FRT supports the role of these tissues in genital anti-microbial immunity and in the control of inflammation while allowing maintenance of its reproductive function.

SUBMITTER: Benjelloun F

PROVIDER: S-EPMC7417306 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings.

Benjelloun Fahd F Quillay Héloïse H Cannou Claude C Marlin Romain R Madec Yoann Y Fernandez Hervé H Chrétien Fabrice F Le Grand Roger R Barré-Sinoussi Françoise F Nugeyre Marie-Thérèse MT Menu Elisabeth E

Frontiers in immunology 20200804

The female reproductive tract (FRT) is the main site of entry of sexually transmitted infections (STIs). Toll-like receptors (TLRs) that recognize pathogenic motifs are widely expressed in the FRT. TLR stimulation induces immune activation and local production of inflammatory mediators. In the FRT, this response should also be compatible with reproductive functions and symbiosis with host microbiota. With a view to develop efficient mucosal vaccines to prevent STI acquisition, the role of TLR li ...[more]

PMID: 32849571

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Project description:BACKGROUND:Environmental exposures are associated with a number of outcomes including adverse pregnancy outcomes. Although inflammation is hypothesized to play a role, the mechanistic pathways between environmental exposures and adverse health outcomes, including associations between exposures and longitudinal measures of systemic and reproductive tract inflammation, need elucidation. OBJECTIVES:This study was conducted to evaluate whether exposure to air pollution is associated with immunologic responses in the systemic circulation and lower reproductive tract, and to evaluate whether systemic and reproductive tract immunologic responses are similar. METHODS:We quantified repeated measures of cytokines from cervico-vaginal exudates and serum obtained concurrently among 104 women with term pregnancies and estimated PM10 and CO exposure using the monitor nearest each participant's residence. Serum and cervico-vaginal cytokines were compared using Wilcoxon signed-ranks test and Spearman rank correlations for select gestational months. We used intraclass correlation coefficients (ICCs) to quantify reproducibility of cytokine measurements, and Tobit regression to estimate associations between air pollution and cytokines. RESULTS:Median cervico-vaginal levels of IL-6, Eotaxin, IP-10, MCP-1, MIP-1?, MIP-1?, and TNF? were higher than corresponding serum cytokines, significantly so for IL-6 and IP-10. Cervico-vaginal and serum cytokines were not correlated, but cytokines from the same fluid were correlated. ICCs for most serum cytokines were ?0.40, while ICCs were higher in cervico-vaginal cytokines (range 0.52-0.83). IP-10 and Eotaxin had the highest ICCs for both cytokine sources. In adjusted models, PM10 was positively associated with serum cytokines IL-6, IP-10, MIP-1? and Eotaxin but inversely associated with cervico-vaginal cytokine TNF?, IP-10, MIP-1?, MCP-1 and Eotaxin, controlling for false discovery rate. CO was inversely associated with cervico-vaginal TNF?, IL-6, MIP-1?, MCP-1 and Eotaxin. CONCLUSIONS:Inflammatory processes are compartment-specific. Systemic inflammatory markers may provide information on immunologic processes and response to environmental exposures, but are not proxies for lower reproductive tract inflammation.

Project description:Adipocytes are the most important cell type in adipose tissue playing key roles in immunometabolism. We previously reported that nine members of the Toll-like receptor (TLR) family are expressed in an originally established porcine intramuscular pre-adipocyte (PPI) cell line. However, the ability of TLR ligands to modulate immunometabolic transcriptome modifications in porcine adipocytes has not been elucidated. Herein, we characterized the global transcriptome modifications in porcine intramuscular mature adipocytes (pMA), differentiated from PPI, following stimulation with Pam3csk4, Poly(I:C) or LPS which are ligands for TLR2, TLR3, and TLR4, respectively. Analysis of microarray data identified 530 (218 up, 312 down), 520 (245 up, 275 down), and 525 (239 up, 286 down) differentially expressed genes (DEGs) in pMA following the stimulation with Pam3csk4, Poly(I:C), and LPS, respectively. Gene ontology classification revealed that DEGs are involved in several biological processes including those belonging to immune response and lipid metabolism pathways. Functionally annotated genes were organized into two groups for downstream analysis: immune response related genes (cytokines, chemokines, complement factors, adhesion molecules, and signal transduction), and genes involved with metabolic and endocrine functions (hormones and receptors, growth factors, and lipid biosynthesis). Differential expression analysis revealed that EGR1, NOTCH1, NOS2, TNFAIP3, TRAF3IP1, INSR, CXCR4, PPARA, MAPK10, and C3 are the top 10 commonly altered genes of TLRs induced transcriptional modification of pMA. However, the protein-protein interaction network of DEGs identified EPOR, C3, STAR, CCL2, and SAA2 as the major hub genes, which were also exhibited higher centrality estimates in the Gene-Transcription factor interaction network. Our results provide new insights of transcriptome modifications associated with TLRs activation in porcine adipocytes and identified key regulatory genes that could be used as biomarkers for the evaluation of treatments having immunomodularoty and/or metabolic functional beneficial effects in porcine adipocytes.

Dataset Information

Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings.

Publications

Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings.

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