We previously demonstrated that allergen-induced airway inflammation and hyper responsiveness (AHR) was enhanced in mice exposed to repeated social stress. We also found that chronic social disruption stress in mice caused impaired glucocorticoid receptor (GR) expression and function in immune cells and in the lung. By other investigators stress was shown to induce abnormal methylation pattern of the GR gene and modified H3K4me3 and H3K27me3 in brain cells of rodents. The significance and mechanisms of the chronic psychosocial stress effects on the GR remain unclear and the currently available chronic models of psychosocial stress in rodents are less than optimal. In non-human primates (rhesus macaques) studied at the CNPRC at UC Davis, inhibited temperament in infant monkeys was associated with blunted cortisol responsiveness and AHR at 2 years of age. We postulate that a heightened predisposition to asthma of chronically stressed rhesus macaques is related to an impaired responsiveness to endogenous glucocorticoids. We further hypothesize that presence of stress (manifested as inhibited temperament) and allergic asthma (elevated IgE, peripheral blood eosinophilia and AHR) increases NF-kB activity that interferes with the GR in immune cells. Epigenetic modifications of the Exon 1 gene promoter reduce GR expression in stressed animals.
Aim 1 is to study whether increased NF-kB activity interferes with GR expression, function and steroid responsiveness of peripheral blood immune cells from primates that exhibit chronic anxiety and asthma. We will compare glucocorticoid responsiveness and expression of GR and NF-kB (a pro-inflammatory transcription factor and GR inhibitor), nuclear translocation and DNA binding in peripheral blood mononuclear cells from these four groups.
Aim 2 is to study the role of epigenetic changes in regulation of GR expression in immune cells of primates that exhibit stress and AHR. We previously found stress-induced reduction in GR mRNA expression in the lung of mice. Stress-induced DNA methylation of NR3C1 and histone modifications was also identified in rodents. In peripheral blood mononuclear cells from rhesus macaques we will correlate abnormal GR expression with gene methylation patterns using DNA methylation mapping and ChIPseq analysis. These studies will lay the groundwork for subsequent investigations into the relevance to human disease and mechanistic studies on the cellular-molecular pathways that lead to asthma predisposition due to psychosocial stress.
Psychosocial stress has severe impact on the course of chronic asthma but the mechanisms are poorly defined. We previously found that asthma exacerbation in stressed mice was related to glucocorticoid insensitivity and decreased glucocorticoid receptor (GR) expression and function. Here we will study stress induced epigenetic modifications of the GR in a well characterized cohort of non-human primates. We aim to identify molecular junctions that link psychosocial stress and asthma.
