Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

Juan Antonio Aguilar-Pimentel,Valérie Gailus-Durner,Yi-Li Cho,Maria Wimmer,Julia Calzada-Wack,Raffaele Gerlini,Raffaele Teperino,Thure Adler,Leena Strauss,Dirk H Busch,Martin Hrabě De Angelis,Helmut Fuchs,Matti Poutanen,Claes Ohlsson,Carsten B Schmidt-Weber,Markus Ollert,Philipp Mayer-Kuckuk

doi:10.1038/s41598-020-75059-9

Abstract

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.

Highlights

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response
Conformation that increased immunoglobulin levels are a direct consequence of an increased estrogen to androgen ratio (E/A) in AROM+ males was obtained from pharmacological inhibition of the aromatase activity resulting in the anticipated normalization of the IgE levels (Fig. 1C)
We report that in the male AROM+ mice, that exhibit high circulating estrogen to androgen ratio, the levels of several immunoglobulin isotypes were increased starting at 60 days of age

Summary

Introduction

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. These data demonstrated that the ratio of estrogen to androgen determines the B cell response These important findings, notwithstanding, have been derived mostly from studies in female mice with altered estrogen levels. To assess the effect of altered estrogen to androgen levels on immune system in males in vivo, we selected the established AROM+ mouse model[11,12] In this model, human aromatase is ubiquitously expressed, resulting in elevated endogenous levels of estradiol and reduced level of testosterone, and estrogen to androgen ratio (E/A) in male mice, yet estrogen levels remain physiological, i.e. similar to female mice. We observed a shifted distribution of B cell subpopulation, an increased B cell proliferation rate in vitro, and changes in the gene expression in different the splenic B cell subpopulations

Methods

Results

Conclusion