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| 2. |
- Antonson, P., et al.
(författare)
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aP2-Cre-Mediated Inactivation of Estrogen Receptor Alpha Causes Hydrometra
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- In this study we describe the reproductive phenotypes of a novel mouse model in which Cre-mediated deletion of ER alpha is regulated by the aP2 (fatty acid binding protein 4) promoter. ER alpha-floxed mice were crossed with transgenic mice expressing Cre-recombinase under the control of the aP2 promoter to generate aP2-Cre/ER alpha(flox/flox) mice. As expected, ER alpha mRNA levels were reduced in adipose tissue, but in addition we also detected an 80% reduction of ER alpha levels in the hypothalamus of aP2-Cre/ER alpha(flox/flox) mice. Phenotypic analysis revealed that aP2-Cre/ER alpha(flox/flox) female mice were infertile. In line with this, aP2-Cre/ER alpha(flox/flox) female mice did not cycle and presented 3.8-fold elevated estrogen levels. That elevated estrogen levels were associated with increased estrogen signaling was evidenced by increased mRNA levels of the estrogen-regulated genes lactoferrin and aquaporin 5 in the uterus. Furthermore, aP2-Cre/ER alpha(flox/flox) female mice showed an accumulation of intra-uterine fluid, hydrometra, without overt indications for causative anatomical anomalies. However, the vagina and cervix displayed advanced keratosis with abnormal quantities of accumulating squamous epithelial cells suggesting functional obstruction by keratin plugs. Importantly, treatment of aP2-Cre/ER alpha(flox/flox) mice with the aromatase inhibitor Letrozole caused regression of the hydrometra phenotype linking increased estrogen levels to the observed phenotype. We propose that in aP2-Cre/ER alpha(flox/flox) mice, increased serum estrogen levels cause over-stimulation in the uterus and genital tracts resulting in hydrometra and vaginal obstruction.
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| 3. |
- Raccosta, L, et al.
(författare)
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Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses
- 2023
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 14:2, s. 129-
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Tidskriftsartikel (refereegranskat)abstract
- Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients.
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| 4. |
- Antonson, P, et al.
(författare)
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Estrogen Receptor-α Knockout Mice
- 2016
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1366, s. 425-430
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Antonson, P., et al.
(författare)
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Generation of an all-exon Esr2 deleted mouse line: Effects on fertility
- 2020
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 529:2, s. 231-237
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor beta (ER beta), encoded by the Esr2 gene, is one of two nuclear receptors that mediate the functions of the steroid hormone estradiol. The binding of estradiol to the receptor results in enhanced transcription of many genes that have estrogen response elements in promoter or enhancer regions. Several genetically modified mouse lines with mutations or deletions of exons in the Esr2 gene have been developed and results from analysis of these are not completely consistent, especially regarding ER beta's role in fertility. To address these controversies, we have used the CRISPR/Cas9 genome editing system to make a deletion of the entire Esr2 gene in the mouse genome and determined the effect of this mutation on fertility. We show that female Esr2 deleted mice, Esr2(Delta E1-10), are subfertile at young age, with fewer litters and smaller litter size, and that they become infertile/have severely reduced fertility at around six months of age, while the male Esr2(Delta E1-10) mice are fertile. Ovaries from Esr2(Delta E1-10) mice are smaller than those from wild-type littermates and the morphology of the ovary displays very few corpora lutea, indicating a defect in ovulation. We also show that the estradiol levels are reduced at diestrus, the phase in the estrous cycle when levels are expected to start to increase before ovulation. Our results verify that ER beta has an important function in female reproduction, likely as a regulator of serum estradiol levels, and that its loss does not affect male reproductive function. (C) 2020 The Authors. Published by Elsevier Inc.
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| 7. |
- Antonson, P., et al.
(författare)
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Identification of proteins highly expressed in uterine fluid from mice with hydrometra
- 2015
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 466:4, s. 650-655
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ER alpha) is an important regulator of the estrous cycle and mice with global ER alpha deletion, as well as some conditional knockout mouse lines, have an interruption in the estrous cycle. In this study we observed that conditional ERa knockout mice where the Cre gene is regulated by the rat insulin promoter (RIP), RIP-Cre/ER alpha(KO) mice, have a 3.7-fold increase in serum 17 beta-estradiol levels, blocked estrous cycle, and develop a fluid-filled uterus (hydrometra). Using a proteomics approach, we identified three proteins, lactoferrin, complement C3 and chitinase 3-like protein 1 (CHI3L1), as highly expressed proteins in hydrometra fluid. The mRNA levels of the corresponding genes were more than 50-fold higher in RIP-Cre/ER alpha(KO) uterus compared to controls. High expression of CHI3L1 in the uterine fluid was not reflected as elevated levels in the serum. The high expression of lactoferrin, complement C3 and CHI3L1 in the uterine fluid, in association with elevated estrogen levels, prompted us to address if the expression of these genes is related to reproduction. However, gonadotropin treatment of mice reduced the uterine expression of these genes in a model of in vitro fertilization. Our findings identify lactoferrin, complement C3 and CHI3L1 as highly expressed proteins in hydrometra fluid in association with chronically elevated serum estradiol levels. (C) 2015 Elsevier Inc. All rights reserved.
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| 8. |
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| 9. |
- Brockmann, L, et al.
(författare)
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Molecular and functional heterogeneity of IL-10-producing CD4+ T cells
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 5457-
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Tidskriftsartikel (refereegranskat)abstract
- IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation.
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