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A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation.

ABSTRACT: Allergic asthma is a chronic inflammatory disease dominated by a CD4+ T helper 2 (Th2) cell signature. The immune response amplifies in self-enforcing loops, promoting Th2-driven cellular immunity and leaving the host unable to terminate inflammation. Posttranscriptional mechanisms, including microRNAs (miRs), are pivotal in maintaining immune homeostasis. Since an altered expression of various miRs has been associated with T cell-driven diseases, including asthma, we hypothesized that miRs control mechanisms ensuring Th2 stability and maintenance in the lung. We isolated murine CD4+ Th2 cells from allergic inflamed lungs and profiled gene and miR expression. Instead of focusing on the magnitude of miR differential expression, here we addressed the secondary consequences for the set of molecular interactions in the cell, the interactome. We developed the Impact of Differential Expression Across Layers, a network-based algorithm to prioritize disease-relevant miRs based on the central role of their targets in the molecular interactome. This method identified 5 Th2-related miRs (mir27b, mir206, mir106b, mir203, and mir23b) whose antagonization led to a sharp reduction of the Th2 phenotype. Overall, a systems biology tool was developed and validated, highlighting the role of miRs in Th2-driven immune response. This result offers potentially novel approaches for therapeutic interventions.

SUBMITTER: K?l?c A

PROVIDER: S-EPMC6124409 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation.

Kılıç Ayşe A Santolini Marc M Nakano Taiji T Schiller Matthias M Teranishi Mizue M Gellert Pascal P Ponomareva Yuliya Y Braun Thomas T Uchida Shizuka S Weiss Scott T ST Sharma Amitabh A Renz Harald H

JCI insight 20180607 11

Allergic asthma is a chronic inflammatory disease dominated by a CD4+ T helper 2 (Th2) cell signature. The immune response amplifies in self-enforcing loops, promoting Th2-driven cellular immunity and leaving the host unable to terminate inflammation. Posttranscriptional mechanisms, including microRNAs (miRs), are pivotal in maintaining immune homeostasis. Since an altered expression of various miRs has been associated with T cell-driven diseases, including asthma, we hypothesized that miRs cont ...[more]

PMID: 29875322

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Project description:ObjectiveTrauma induces a complex immune response that requires a systems biology research approach. Here, we used a novel technology, mass cytometry by time-of-flight, to comprehensively characterize the multicellular response to trauma.DesignPeripheral blood mononuclear cells samples were stained with a 38-marker immunophenotyping cytometry by time-of-flight panel. Separately, matched peripheral blood mononuclear cells were stimulated in vitro with heat-killed Streptococcus pneumoniae or CD3/CD28 antibodies and stained with a 38-marker cytokine panel. Monocytes were studied for phagocytosis and oxidative burst.SettingSingle-institution level 1 trauma center.Patients or subjectsTrauma patients with injury severity scores greater than 20 (n = 10) at days 1, 3, and 5 after injury, and age- and gender-matched controls.InterventionsNone.Measurements and main resultsTrauma-induced expansion of Th17-type CD4 T cells was seen with increased expression of interleukin-17 and interleukin-22 by day 5 after injury. Natural killer cells showed reduced T-bet expression at day 1 with an associated decrease in tumor necrosis factor-β, interferon-γ, and monocyte chemoattractant protein-1. Monocytes showed robust expansion following trauma but displayed decreased stimulated proinflammatory cytokine production and significantly reduced human leukocyte antigen - antigen D related expression. Further analysis of trauma-induced monocytes indicated that phagocytosis was no different from controls. However, monocyte oxidative burst after stimulation increased significantly after injury.ConclusionsUsing cytometry by time-of-flight, we were able to identify several major time-dependent phenotypic changes in blood immune cell subsets that occur following trauma, including induction of Th17-type CD4 T cells, reduced T-bet expression by natural killer cells, and expansion of blood monocytes with less proinflammatory cytokine response to bacterial stimulation and less human leukocyte antigen - antigen D related. We hypothesized that monocyte function might be suppressed after injury. However, monocyte phagocytosis was normal and oxidative burst was augmented, suggesting that their innate antimicrobial functions were preserved. Future studies will better characterize the cell subsets identified as being significantly altered by trauma using cytometry by time-of-flight, RNAseq technology, and functional studies.

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A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation.

Publications

A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation.

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