A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation
Ayşe Kılıç, … , Amitabh Sharma, Harald Renz
Ayşe Kılıç, … , Amitabh Sharma, Harald Renz
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e97503. https://doi.org/10.1172/jci.insight.97503.
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Research Article Immunology Inflammation

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.

Authors

Ayşe Kılıç, Marc Santolini, Taiji Nakano, Matthias Schiller, Mizue Teranishi, Pascal Gellert, Yuliya Ponomareva, Thomas Braun, Shizuka Uchida, Scott T. Weiss, Amitabh Sharma, Harald Renz

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Figure 2

Isolation of live CD4+ Th cell subsets from allergic inflamed lungs using FACS.

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Isolation of live CD4+ Th cell subsets from allergic inflamed lungs usin...
(A) Heatmap representation of expression of naive T cell and Th-subset-specific genes. (B) Cytokine expression of FACS-isolated 2 × 105 Th1 and Th2 cells. (C) Venn diagram comparing upregulated genes detected in memory Th2 cells with previously published lung Th2 memory data sets. IL-5+ memory (mem) (DO11.10 cells polarized to Th2 in vitro and expanded in vivo, GSE33516 data set), CD4+ T cells from house dust mite–induced (HDM-induced) allergic airway inflammation (GSE72005 data set). Changes in gene expression were determined by comparing to the respective control population of each experimental setting with a cutoff of 2-fold. (D) Volcano plot representation of gene expression differences between naive CD4+ T cells and early Th2 cells. Lineage-specific genes are highlighted in color. Dashed lines indicate cutoff levels for gene expression (log2-fold > 1) and significance (P < 0.05). (E) Volcano plot representation of gene expression changes from early to stable Th2 (memory) cells. (F) Heatmap depicting differentially expressed transcription factors. n = 3 independent experiments. Cells were pooled from 10–12 mice. (D and E) Fold change in expression was calculated with mean values for each group.