Estrogen Receptor Alpha Binding to ERE is Required for Full Tlr7- and Tlr9-Induced Inflammation

Cunningham, Melissa A.; Wirth, Jena R.; Naga, Osama; Eudaly, Jackie; Gilkeson, Gary S.

doi:10.15226/soji.2014.00107

Cited by 24 publications

(19 citation statements)

References 23 publications

(18 reference statements)

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“…First, differences in sex hormones in gonadally intact females versus males presents a major confound when studying sex chromosome effects, a confound not present in our studies which used GDX mice of the FCG model. Indeed, many studies have established a role of estrogen on B cells in SLE (humans and mice) (77), and TLR7 function is affected by interactions between estrogen receptor-α and estrogen response elements (78). Second, previously observed biallelic expression of Tlr7 in B lymphocytes was found in cells that were not in vitro-stimulated (74–76, 79).…”

Section: Discussionmentioning

confidence: 99%

Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes

Golden

Itoh

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Many autoimmune diseases are more frequent in females than in males in humans and their mouse models, and sex differences in immune responses have been shown. Despite extensive studies of sex hormones, mechanisms underlying these sex differences remain unclear. Here, we focused on sex chromosomes using the “four core genotypes” model in C57BL/6 mice and discovered that the transcriptomes of both autoantigen and anti-CD3/CD28 stimulated CD4+T lymphocytes showed higher expression of a cluster of 5 X genes when derived from XY as compared to XX mice. We next determined if higher expression of an X gene in XY compared to XX could be due to parent-of-origin differences in DNA methylation of the X chromosome. We found a global increase in DNA methylation on the X chromosome of paternal as compared to maternal origin. Since DNA methylation usually suppresses gene expression, this result was consistent with higher expression of X genes in XY cells because XY cells always express from the maternal X chromosome. In addition, gene expression analysis of F1 hybrid mice from CAST × FVB reciprocal crosses showed preferential gene expression from the maternal X compared to paternal X chromosome, revealing that these parent-of-origin effects are not strain-specific. SJL mice also showed a parent-of-origin effect on DNA methylation and X gene expression; however, which X genes were affected differed from those in C57BL/6. Together, this demonstrates how parent-of-origin differences in DNA methylation of the X chromosome can lead to sex differences in gene expression during immune responses.

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Section: Discussionmentioning

confidence: 99%

Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes

Golden

Itoh

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Activation of TLR4, caspase-1, IL-1β, and mast cells are also known to increase myocarditis and promote remodeling, fibrosis, and DCM in CVB3 myocarditis in male mice (44, 54) suggesting that BPA exposure could increase the risk of progression from myocarditis to DCM and heart failure in women. Importantly, ERα has been found to modulate TLR expression including TLR 2, 7, 8, and 9 (11, 27, 73, 74) while ERα has been found to decrease TLR4 (35).…”

Section: Discussionmentioning

confidence: 99%

BPA Alters Estrogen Receptor Expression in the Heart After Viral Infection Activating Cardiac Mast Cells and T Cells Leading to Perimyocarditis and Fibrosis

et al. 2019

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Myocarditis is an inflammatory heart disease that leads to dilated cardiomyopathy (DCM) and heart failure. Sex hormones play an important role in the development of myocarditis with testosterone driving disease in males and estrogen being cardioprotective in females. The human population is widely exposed to the endocrine disruptor bisphenol A (BPA) from plastics such as water bottles, plastic food containers, copy paper, and receipts. Several clinical and numerous animal studies have found an association between elevated BPA levels and cardiovascular disease. A recent report found elevated levels of BPA in the serum of patients with DCM compared to healthy controls. In this study we examined whether exposure to BPA for 2 weeks prior to viral infection and leading up to myocarditis at day 10 altered inflammation in female BALB/c mice housed in standard plastic cages/water bottles with soy-free food and bedding. We found that a human relevant dose of BPA (25 μg/L) in drinking water, with an estimated exposure of 5 μg BPA/kg BW, significantly increased myocarditis and pericarditis compared to control water without altering viral genome levels in the heart. BPA exposure activated ERα and ERβ in the spleen 24 h after infection and phosphorylated ERα and ERβ during myocarditis, but decreased ERα and increased ERβ mRNA in the heart as measured by qRT-PCR. Exposure to BPA significantly increased CD4+ T cells, IFNγ, IL-17A, TLR4, caspase-1, and IL-1β in the heart. BPA exposure also increased cardiac fibrosis compared to controls. Mast cells, which are associated with cardiac remodeling, were found to increase in number and degranulation, particularly along the pericardium. Interestingly, plastic caging/water bottle exposure alone led to increased mast cell numbers, pericardial degranulation and fibrosis in female BALB/c mice compared to animals housed in glass cages/water bottles with soy-free food and bedding. These data suggest that BPA exposure may increase the risk of developing myocarditis after a viral infection in women.

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“…Investigation of mechanisms by which ligand-bound ERs modulate gene expression programs in immune cells or their precursors will increase our understanding of how estrogens modulate immunity. While recent studies of AF-1- or AF-2-deficient mice, and mice bearing an ERα mutant that cannot bind ERE, have advanced this field [ 32 , 33 ], we still lack a detailed understanding of the mechanisms of ER-mediated nuclear or MISS responses in innate immunity.…”

Section: Er Signaling Mechanismsmentioning

confidence: 99%

Estrogen receptors regulate innate immune cells and signaling pathways

Kovats

2015

Cellular Immunology

763

590

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Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ER) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol most often promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells.

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Estrogen Receptor Alpha Binding to ERE is Required for Full Tlr7- and Tlr9-Induced Inflammation

Cited by 24 publications

References 23 publications

Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes

Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes

BPA Alters Estrogen Receptor Expression in the Heart After Viral Infection Activating Cardiac Mast Cells and T Cells Leading to Perimyocarditis and Fibrosis

Estrogen receptors regulate innate immune cells and signaling pathways

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