Lung pro-inflammatory microRNA and cytokine expression in a mouse model of allergic inflammation: role of sex chromosome complement and gonadal hormones.

Epigenetic alterations such as dysregulation of microRNAs (miRNAs) have been reported to play important roles in interactions between genetic and environmental factors. In this study, we tested the hypothesis that induction of lung inflammation by inhaled allergens triggers a sex-specific miRNA regulation that is dependent on chromosome complement and hormonal milieu. We challenged the four core genotypes (FCG) model through intranasal sensitization with a house dust mite (HDM) solution (or PBS as a control) for 5 weeks. The FCG model allows four combinations of gonads and sex chromosomes: 1) XX mice with ovaries (XXF), 2) XY mice with testes (XYM), 3) XX mice with testes (XXM), and 4) XY mice with ovaries (XYF). Following challenge (n=5-7/group), we assessed the expression of 84 inflammatory miRNAs in lung tissue using a PCR array and cytokine levels in bronchoalveolar lavage fluid (BAL) by a multiplex protein assay (n=4-7/group). Our results showed higher levels of the chemokine, KC (an Il-8 homologue) and IL-7 in BAL from XYF mice challenged with HDM. Additionally, IL-17A was significantly higher in BAL from both XXF and XYF. A three-way interaction between treatment, gonads and sex chromosome revealed 60/64 miRNAs that differed in expression depending on genotype; XXF, XXM, XYF and XYM had 45, 32, 4 and 52 differentially expressed miRNAs respectively. Regulatory networks of miRNAs identified in this study were implicated in pathways associated with asthma. Female gonadal hormonal effects may alter miRNA expression and contribute to higher susceptibility of females to asthma.