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

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.

SUBMITTER: Aguilar-Pimentel JA

PROVIDER: S-EPMC7591566 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Aguilar-Pimentel Juan Antonio JA Cho Yi-Li YL Gerlini Raffaele R Calzada-Wack Julia J Wimmer Maria M Mayer-Kuckuk Philipp P Adler Thure T Schmidt-Weber Carsten B CB Busch Dirk H DH Fuchs Helmut H Gailus-Durner Valérie V Ollert Markus M Hrabě de Angelis Martin M Ohlsson Claes C Poutanen Matti M Teperino Raffaele R Strauss Leena L

Scientific reports 20201027 1

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+). Th ...[more]

PMID: 33110090

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Project description:Urinary tract infections (UTIs) in men are uncommon yet carry an increased risk for severe pyelonephritis and other complications. In models of Escherichia coli UTI, C3H/HeN mice develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by a reduction of neutrophil function within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenic E. coli (UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101-). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced function in vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Furthermore, aged immature neutrophils manifested little phagocytic activity within intratubular UPEC communities in vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens is attributable, at least in part, to local impairment of neutrophil maturation in the urinary tract (largely via cell-intrinsic AR signaling) and a kidney-specific reduction in neutrophil antimicrobial capacity.IMPORTANCEAlthough urinary tract infections (UTIs) predominantly occur in women, male UTIs carry an increased risk of morbidity and mortality. Pyelonephritis in androgen-exposed mice features robust neutrophil recruitment and abscess formation, while bacterial load remains consistently high. Here, we demonstrate that during UTI, neutrophils infiltrating the urinary tract of androgen-exposed mice exhibit reduced maturation, and those that have infiltrated the kidney have reduced phagocytic and degranulation functions, limiting their ability to effectively control infection. This work helps to elucidate mechanisms by which androgens enhance UTI susceptibility and severity, illuminating why male patients may be predisposed to severe outcomes of pyelonephritis.

Project description:BackgroundOccupational exposures to chromium (Cr), which can have adverse effects on immune function, have not yet been extensively investigated. Hexavalent chromium (Cr (VI)), used in mineral tanning processes, poses a threat to the health of workers in the leather tanning industry.ObjectivesThe aim of the present study was to evaluate the effects of long-term Cr exposure on the physical health and immunological parameters of male tannery workers in Bangladesh compared with a control group.MethodsA health examination was performed with tannery workers (N=195) and control subjects (N=125) by physicians, demographic data were recorded in questionnaires and peripheral blood samples were collected. Serum Cr levels were analyzed by an atomic absorption spectrophotometer (AAS), immunoglobulin (Ig)G, IgA, and complement components C3 and C4 were determined by nephelometry, IgE was measured by sandwich enzyme-linked immunosorbent assay and complement function was assayed by bactericidal activity.ResultsThe mean duration of work exposure for the tanners was 9.4±7.1 years. Their body mass index (21.8±3.0 kg/m2), was not significantly different from the controls (22.7±3.2 kg/m2). The mean serum level of Cr in 30 long-term exposed tannery workers (26.97±21.11 μg/dL) was significantly higher than that of 30 randomly selected control subjects (7.38±6.81 μg/dL). The tannery workers had rough skin, rashes, itchy and decolorized skin, allergic diseases and respiratory illness, and had significantly lower levels of serum IgG, IgA, C3 and C4, but significantly higher levels of IgE than the controls. IgG, IgA and C3 levels were all inversely associated with Cr, while IgG, IgE and bactericidal activity showed an inverse correlation with duration of exposure.ConclusionsThe results of the present study suggest that chronic exposure to Cr is associated with impaired immune function in male tannery workers.Participant consentObtained.Ethics approvalThe present study was approved by the Ethical Review Committee of the faculty of Biological Sciences, University of Dhaka, Bangladesh.Competing interestsThe authors declare no competing financial interests.

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

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

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