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MiR-155 deficiency alters heterogeneity of lung immune cells in a mouse model of severe asthma

ABSTRACT: The lung is a complex tissue comprised of more than 40 cell populations. The interplay among the heterogeneous pulmonary cells is required for proper function and long-term maintenance of lung homeostasis. Because each of the cell populations has a distinct transcriptome, bulk RNA-seq could mask cell-cell crosstalk, cell-type-specific contributions, and relevant networking changes in the lung. To overcome the limitations of bulk tissue analysis, we performed single cell RNA sequencing (scRNA-seq) to investigate the transcriptional profiles of lungs affected by miR-155. Unsupervised clustering analysis revealed 27 different clusters corresponding to distinct cell types of the lung, including epithelial, stromal, endothelial, and leukocyte lineages with specific molecular markers. The miR-155 knockout mice subjected to the severe asthma model showed a decrease in lung immune cells, whereas the numbers of structural cells such as epithelial and endothelial cells were slightly increased compared to their wild type counterparts. We also showed that the transcripts of extracellular trap formation-related genes were substantially down-regulated in miR-155 knockout mice subjected to the severe asthma model.

ORGANISM(S): Mus

PROVIDER: GSE203656 | GEO | 2022/07/21

REPOSITORIES: GEO

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Project description:Mechanisms underlying in utero fetal lung injury remain poorly defined, and a greater understanding of pathways regulating these processes may lead to novel therapies that prevent lung injury before birth. MicroRNAs (miRNAs) are small non-coding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. We sought to determine whether differentially expressed miRNAs in the fetal lung following choriodecidual infection are associated with elevation of amniotic fluid (AF) cytokine levels and acute lung injury in a nonhuman primate model. After inoculating ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) with either Group B Streptococcus (GBS) 1 x 106 colony forming units (n=5) or saline (n=5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled changes in expression. We identified 9 differentially expressed miRNAs (p<0.05, >1.5 fold change) in the GBS-exposed fetal lungs by microarray, but of these only miR-155-5p was significantly elevated by qRT-PCR (p=0.016). The microarray log2 intensity of miR-155-5p positively correlated with fetal lung injury scores and AF IL-1? and TNF-??levels (R2=0.54, p=0.016). In situ hybridization revealed that miR-155-5p is expressed throughout the fetal lung, which led us to investigate mechanisms that regulate miR-155-5p expression. Significantly elevated miR-155-5p expression was observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to IL-6 and TNF-??. Overexpression of miR-155-5p in FeAE cells increased production of IL-6, CCL5/RANTES and CXCL10/IP-10. Using a luciferase reporter assay, we validated FGF9 as an authentic target of miR-155-5p, which is essential to development of the lung mesenchyme and distal epithelial branching. Collectively, these results suggest that a choriodecidual inflammatory response leads to increased AF cytokine levels, which induce miR-155-5p expression. In turn, miR-155-5p activates and recruits leukocytes (IL-6, CCL5/RANTES) and inhibits fetal lung angiogenesis (CXCL10/IP-10), meschenchymal development and epithelial branching (targets FGF9 mRNA). A therapy to antagonize miR-155-5p may ameliorate perinatal lung injury.

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MiR-155 deficiency alters heterogeneity of lung immune cells in a mouse model of severe asthma

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