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Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14⁺CD16⁺ Monocytes and ?? T Lymphocytes.

ABSTRACT: Toll-like receptor (TLR)7/8 plays a crucial role in host recognition/response to viruses and its mucosal expression directly correlates with intestinal inflammation. The aim of this study was to investigate the role of TLR7/8 stimulation of intestinal epithelium in shaping the phenotype and functions of innate immunity cell subsets, and to define direct and/or epithelial cell-mediated mechanisms of the TLR7/8 agonist R848 immunomodulatory activity. We describe novel, TLR8-mediated, pro- and anti-inflammatory effects of R848 on ex vivo cultured human blood monocytes and ?? T lymphocytes, either induced by direct immune cell stimulation or mediated by intestinal epithelial cells (IEC). Apical stimulation with R848 led to its transport across normal polarized epithelial cell monolayer and resulted in the inhibition of monocyte differentiation toward immunostimulatory dendritic cells and Th1 type response. Furthermore, ?? T lymphocyte activation was promoted following direct exposure of these cells to the agonist. Conversely, a selective enrichment of the CD14⁺CD16⁺ monocyte subpopulation was observed, which required a CCL2-mediated inflammatory response of normal epithelial cells to R848. Of note, a TLR-mediated activation of control ?? T lymphocytes was promoted by inflamed intestinal epithelium from active Crohn's disease patients. This study unravels a novel regulatory mechanism linking the activation of the TLR8 pathway in IEC to the monocyte-mediated inflammatory response, and highlights the capacity of the TLR7/8 agonist R848 to directly enhance the activation of ?? T lymphocytes. Overall these results expand the range of cell targets and immune responses controlled by TLR8 triggering that may contribute to the antiviral response, to chronic inflammation, as well as to the adjuvant activity of TLR8 agonists, highlighting the role of intestinal epithelium microenvironment in shaping TLR agonist-induced responses.

SUBMITTER: Angelini C

PROVIDER: S-EPMC5743793 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14<sup>+</sup>CD16<sup>+</sup> Monocytes and γδ T Lymphocytes.

Angelini Costanza C Varano Barbara B Puddu Patrizia P Fiori Maurizio M Baldassarre Antonella A Masotti Andrea A Gessani Sandra S Conti Lucia L

Frontiers in immunology 20171222

Toll-like receptor (TLR)7/8 plays a crucial role in host recognition/response to viruses and its mucosal expression directly correlates with intestinal inflammation. The aim of this study was to investigate the role of TLR7/8 stimulation of intestinal epithelium in shaping the phenotype and functions of innate immunity cell subsets, and to define direct and/or epithelial cell-mediated mechanisms of the TLR7/8 agonist R848 immunomodulatory activity. We describe novel, TLR8-mediated, pro- and anti ...[more]

PMID: 29312324

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Project description:BackgroundEvidence on the changes in the absolute counts of monocyte subpopulations in sepsis is missing.MethodsFirstly, absolute counts of circulating CD14pos/HLA-DRpos/CD45pos monocytes were measured by flow cytometry in 70 patients with Gram-negative sepsis and in 10 healthy volunteers. In the second phase, immunophenotyping was performed and the absolute count of circulating inflammatory monocytes and of circulating CD14dim/CD16pos/CD45pos patrolling monocytes were measured in another 55 patients and 10 healthy volunteers. Measurements were repeated on days 3, 7, and 10. Results were correlated with survival after 28 days.ResultsGreater numbers of CD14pos/HLA-DRpos/CD45pos monocytes were found on day 1 in survivors compared to nonsurvivors (p = 0.030). Receiver operating characteristic (ROC) analysis showed that a cutoff higher than 337 cells/mm3 on day 1 could discriminate between survivors and nonsurvivors with a positive predictive value (PPV) of 91.1%. Logistic regression including Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score showed that an absolute count greater than 337 cells/mm3 was independently associated with unfavorable outcome (odds ratio (OR) 0.19, p = 0.050). The absolute counts of inflammatory and of CD14dim/CD16pos/CD45pos monocytes were greater in patients than healthy controls during the entire 10 days of follow-up. The absolute counts on day 3 of CD14dim/CD16pos/CD45pos monocytes were greater in survivors than nonsurvivors (p = 0.027). ROC analysis revealed that the cutoff at 27 cells/mm3 could discriminate between survivors and nonsurvivors with PPV of 94.1%. Logistic regression including age, SOFA score, and APACHE II score showed that an absolute count greater than 27 cells/mm3 was independently associated with unfavorable outcome (OR 0.06, p = 0.033). Logistic regression analysis showed that intra-abdominal infection on day 1 was predictive of low CD14dim/ CD16pos/CD45pos count on day 3.ConclusionCirculating counts of inflammatory and patrolling monocytes are greatly increased in Gram-negative sepsis. Absolute counts of CD14pos/HLA-DRpos/CD45pos monocytes on day 1 and CD14dim/CD16pos/CD45pos monocytes on day 3 are independently associated with final outcome.Trial registrationClinicalTrials.gov, NCT01223690 . Registered retrospectively on 18 October 2010.

Dataset Information

Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14⁺CD16⁺ Monocytes and ?? T Lymphocytes.

Publications

Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14<sup>+</sup>CD16<sup>+</sup> Monocytes and γδ T Lymphocytes.

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Dataset Information

Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14+CD16+ Monocytes and ?? T Lymphocytes.

Publications

Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14<sup>+</sup>CD16<sup>+</sup> Monocytes and γδ T Lymphocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Direct and Intestinal Epithelial Cell-Mediated Effects of TLR8 Triggering on Human Dendritic Cells, CD14⁺CD16⁺ Monocytes and ?? T Lymphocytes.