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Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity.

ABSTRACT: Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.

SUBMITTER: Garavelli S

PROVIDER: S-EPMC7013659 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity.

Garavelli Silvia S Bruzzaniti Sara S Tagliabue Elena E Prattichizzo Francesco F Di Silvestre Dario D Perna Francesco F La Sala Lucia L Ceriello Antonio A Mozzillo Enza E Fattorusso Valentina V Mauri Pierluigi P Puca Annibale A AA Franzese Adriana A Matarese Giuseppe G Galgani Mario M de Candia Paola P

International journal of molecular sciences 20200111 2

Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative R ...[more]

PMID: 31940853

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Project description:BackgroundThe rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.MethodsClusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.ResultsWe identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.ConclusionsOur results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.

Project description:BackgroundTrauma causes tissue injury that results in the release of damage associated molecular patterns (DAMPs) and other mediators at the site of injury and systemically. Such mediators disrupt immune system homeostasis and may activate multicellular immune responses with downstream complications such as the development of infections and sepsis. To characterize these alterations, we used time-of-flight mass cytometry to determine how trauma plasma affects normal peripheral blood mononuclear cell (PBMC) activation to gain insights into the kinetics and nature of trauma-induced circulating factors on human immune cell populations. A better understanding of the components that activate cells in trauma may aid in the discovery of therapeutic targets.MethodsPBMCs from healthy volunteers were cultured with 5% plasma (healthy, trauma-1day, or trauma-3day) or known DAMPs for 24 h. Samples were stained with a broad immunophenotyping CyTOF antibody panel. Multiplex (Luminex) cytokine assays were used to measure differences in multiple cytokine levels in healthy and trauma plasma samples.ResultsPlasma from day 1, but not day 3 trauma patients induced the acute expansion of CD11c+ NK cells and CD73+/CCR7+ CD8 T cell subpopulations. Additionally, trauma plasma did not induce CD4+ T cell expansion but did cause a phenotypic shift towards CD38+/CCR7+ expressing CD4+ T cells. Multiplex analysis of cytokines by Luminex showed increased levels of IL-1RA, IL-6 and IL-15 in trauma-1day plasma. Similar to trauma day 1 plasma, PBMC stimulation with known DAMPs showed activation and expansion of CD11c+ NK cells.ConclusionsWe hypothesized that circulating factors in trauma plasma would induce phenotypic activation of normal human immune cell subsets. Using an unbiased approach, we identified specific changes in immune cell subsets that respond to trauma plasma. Additionally, CD11c+ NK cells expanded in response to DAMPs and LPS, suggesting they may also be responding to similar components in trauma plasma. Collectively, our data demonstrate that the normal PBMC response to trauma plasma involves marked changes in specific subsets of NK and CD8+ T cell populations. Future studies will target the function of these trauma plasma reactive immune cell subsets. These findings have important implications for the field of acute traumatic injuries.

Dataset Information

Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity.

Publications

Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity.

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