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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

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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 1

CD4+ST2+ Th2 cells accumulate in allergic inflamed lung tissue.

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CD4+ST2+ Th2 cells accumulate in allergic inflamed lung tissue.
(A) Flow...
(A) Flow cytometric analysis of CD4+ T cells isolated from spleen, lymph node (LN), and inflamed lung tissue for the presence of CXCR3+ Th1 and ST2+ Th2 cells in the acute and chronic phase. Data are shown as percentage CD4+ T cells and are representative of 3 independent experiments. For the analysis, n = 3–4 mice were pooled per experiment. (B) Flow cytometric analysis of intracellular cytokine production in CD4+ T cells isolated from acute and chronic inflamed lungs. The frequencies of (C) total Th2 and (D) tissue-resident Th2 cells were determined in OVA-induced acute and chronic allergic inflamed lung tissues using flow cytometry. (E) Tissue-resident CD4+ T cells isolated from spleen, LN, and lung were stained for naive (CD62L) and memory markers (CD44). Values are presented as percentage of the parental population (upper panel: CD4+CD69+; lower panel: CD4+CD69–). Data are representative of 2 independent experiments with n = 3–4 mice per experiment. Graphs (C and D) depict mean ± SEM of 3 independent experiments each with 3–4 animals per group. *P < 0.05, **P < 0.01, *** P < 0.001, by (C) 2-tailed Mann-Whitney U test and (D) ANOVA followed by Tukey’s post test.

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