A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation
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
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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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 4

Th2 differentially expressed genes form disease modules in the miR-interactome network.

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Th2 differentially expressed genes form disease modules in the miR-inter...
(A) Workflow of the methodology used to prioritize miRs relevant to the Th2 phenotype. Expression data were collected and differentially expressed genes and miRs were mapped to the human miR-interactome, resulting in a stable and an early disease module. We developed the Impact of Differential Expression Across Layers (IDEAL) methodology to prioritize miRs that target topologically central genes in the respective disease modules. A collective of 5 miRs was found to have maximum impact in the stable Th2 condition. These miRs were ultimately validated in mice. (B) Genes differentially expressed in stable Th2 cells above a certain fold-change (FC) cutoff are mapped onto the interactome. The size of the obtained largest connected component (LCC) is compared to that of a random set of genes of the same size, resulting in a Z score. This procedure is repeated for multiple cutoffs. A maximum connectivity is observed for FC = 1.3. (C) Same as B, for the early condition. An optimal cutoff of 1.9 is found. (D) The impact of differentially expressed miRs of the Th2 disease modules is assessed by removing their targets having opposite FC. The Z score of the resulting modules are shown by red beans and are nonsignificant (below the red dashed line corresponding to 95% CI). However, the modules show high robustness to the removal of the same number of randomly picked nodes, simulating random attacks, with Z scores consistently significant (gray beans).