Chronic psychological stress potentiates IgE class switch recombination via glucocorticoid receptor-mediated...

Chronic psychological stress is a well-recognized factor in the exacerbation of allergic diseases, with IgE playing a central role in their pathophysiology. However, the exact molecular mechanisms by which stress hormones directly influence IgE production and contribute to allergic responses remain largely uncharacterized.

This study aimed to elucidate the direct mechanisms through which chronic psychological stress, via elevated cortisol, regulates IgE class switch recombination (CSR) in B cells and contributes to stress-aggravated allergic inflammation in vivo.

We employed a chronic restraint stress (CRS) mouse model to investigate the impact of psychological stress on humoral immunity. In vitro experiments utilized primary murine B cells treated with physiological cortisol concentrations (250 nM), incorporating molecular techniques such as CRISPR-Cas9-mediated gene knockdown, chromatin immunoprecipitation (ChIP), whole-genome bisulfite sequencing, and pharmacological inhibitors of epigenetic enzymes. Primary human B cells and the U266 human myeloma cell line were used for translational validation. In vivo validation was performed using an ovalbumin (OVA)-induced allergic airway inflammation model with B cell-specific glucocorticoid receptor (GR) knockout mice.

Chronic psychological stress significantly elevated plasma corticosterone and serum IgE levels in mice, with no changes in IgG1 or IgM. In purified in vitro B-cell cultures, cortisol promotes epigenetic remodeling at the Iε promoter region and enhances Iε germline transcript expression in an isotype-specific manner, and this effect was recapitulated in human B cells. GR bound to the Iε promoter's Amp_1 region (-154 to -62 bp), and CRISPR-Cas9-mediated GR knockdown abolished cortisol-induced IgE production. Mechanistically, cortisol increases enrichment of activating histone marks (H3K27ac, H3K4me3) and reduces H3K27me3 at the Iε promoter region, and induces site-specific DNA hypomethylation; inhibition of histone acetyltransferases (HATs) or DNA demethylation attenuated this effect. In vivo, B cell-specific GR knockout completely abrogated stress-induced exacerbation of allergic airway inflammation, including elevated serum IgE, eosinophilic inflammation, and airway hyperresponsiveness (AHR).

Our findings support a mechanistic model in which chronic psychological stress, through elevated glucocorticoids, acts via GR to promote epigenetic remodeling at the Iε promoter region in B cells to enhance IgE synthesis and exacerbate allergic responses. This study provides a critical molecular link between the neuroendocrine system and adaptive immunity, offering promising therapeutic targets for stress-aggravated IgE-mediated diseases.