Choriodecidual Group B Streptococcal Infection Induces miR-155-5p in the Fetal Lung in Macaca nemestrina

Abstract

eThe mechanisms underlying fetal lung injury remain poorly defined. MicroRNAs (miRNAs) are small noncoding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. Using a nonhuman primate model of choriodecidual infection, we sought to determine if differentially expressed miRNAs were associated with acute fetal lung injury. After inoculating 10 chronically catheterized pregnant monkeys (Macaca nemestrina) with either group B streptococcus (GBS) at 1 ؋ 10 6 CFU (n ‫؍‬ 5) or saline (n ‫؍‬ 5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled the changes in expression by microarray analysis. We identified 9 differentially expressed miRNAs in GBS-exposed fetal lungs, but of these, only miR-155-5p was validated by quantitative reverse transcription-PCR (P ‫؍‬ 0.02). Significantly elevated miR-155-5p expression was also observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to proinflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-␣]). Overexpression of miR-155-5p in FeAE cells in turn increased the production of IL-6 and CXCL10/gamma interferon-induced protein 10, which are implicated in leukocyte recruitment but also in protection from lung injury. Interestingly, while miR-155-5p decreased fibroblast growth factor 9 (FGF9) expression in a luciferase reporter assay, FGF9 levels were actually increased in GBS-exposed fetal lungs in vivo. FGF9 overexpression is associated with abnormal lung development. Thus, upregulation of miR-155-5p may serve as a compensatory mechanism to lessen the increase in FGF9 and prevent aberrant lung development. Understanding the complicated networks regulating lung development in the setting of infection is a key step in identifying how to prevent fetal lung injury leading to bronchopulmonary dysplasia.

MicroRNAs in mucosal inflammation

“…In contrast to the miRNAs reported in the previous paragraph, miR-155 was found to act pro-inflammatory in acute lung injury [90], which is in accordance with its role reported in other inflammatory disease. Inducing acute fetal lung injury in a nonhuman primate model of choriodecidual infection, analysis of changes in fetal lung gene expression revealed significant changes in miR-155 expression.…”

“…Inducing acute fetal lung injury in a nonhuman primate model of choriodecidual infection, analysis of changes in fetal lung gene expression revealed significant changes in miR-155 expression. Similarly, miR-155 expression level changes have been observed in cytokine stimulated fetal airway epithelial (FeAE) cells [90]. Functional studies using mucosal overexpression of miR-155 led to increased epithelial production of pro-inflammatory cytokines, such as Interleukin-6 (IL-6) and interferon (IFN)-γ inducible protein (CXCL10/IP-10).…”

MicroRNA Regulation of Acute Lung Injury and Acute Respiratory Distress Syndrome

“…Furthermore, the authors also found that C/EBPb (CCAAT/enhancer-binding protein beta), a target molecule of miR-155, was associated with IL-10secreting M2-like phenotype of macrophages (Guo et al, 2013a). In support of the above finding, Rao et al (2014) and McAdams et al (2015) illustrated increased expression of miR-155 in SEB (Staphylococcal enterotoxin B) and choriodecidual group B streptococcal infected lungs, respectively. Rao et al (2014) compared the development of ALI in wild-type and miR-155 À/À mice and found that miR-155 À/À had diminished inflammatory cytokines production and inflammatory cells accumulation in SEB-infected lungs.…”

“…Interestingly, this finding is in agreement with the report of Androulidaki et al () that miR‐155 mimic suppresses SOCS1 expression in vitro. Later, McAdams et al () showed that over‐expression of miR‐155‐5p in fetal airway epithelial cells in turn increased the production of IL‐6 and CXCL10/IP‐10 (C‐X‐C motif ligand 10), which are implicated in leukocyte recruitment. Together, these studies suggested an important role for miR‐155 in promoting inflammation in the lungs in response to different injury models.…”

Perinatal Group B Streptococcal Infections: Virulence Factors, Immunity, and Prevention Strategies

“…Fetal lung injury can also be caused by GBS-induced chorioamnionitis without bacterial invasion [38, 105]. Also, increases in amniotic fluid cytokines contributes to fetal lung injury [38], and dysregulation of fetal lung development [105] [106]. Moreover, intra-amniotic administration of MVs leads to significantly increased rates of fetal damage and preterm birth [84].…”