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Aim: A more vigorous immune system activation is generally seen in women as compared to men. The reasons for these differences are still not understood. By investigating the immune-regulatory role of estrogens, we have previously shown that estradiol (E2) can regulate and ameliorate rheumatoid arthritis models. The aim of this study was to elucidate the role of ovariectomy (ovx) and estradiol (E2) in innate immune responses., Methods: Female mice were ovx or sham operated. After three weeks, either dorsal air pouches were established by injections of sterile air with subsequent lipopolysaccharide (LPS) injection, or LPS was injected intra-peritoneally (i.p). Mice received daily injections with E2 or vehicle for three days before challenge. 6 hours after challenge in the air pouch, blood cells were counted, leukocytes from the pouch were analyzed by flow cytometry, and cytometric bead array or ELISA were used to quantify cytokines collected from the air pouch. Blood cells were counted 1h after i.p challenge., Results: Compared to sham, blood leukocyte numbers increased after ovx and ovx+E2 6 h after LPS injections into the air pouch. LPS after ovx induced neutrophil infiltration into the pouch, accompanied by increased levels of MCP-1 and IL-6. Ovx+E2 further enhanced cell infiltration after LPS; however, the cell population diversified by also including more macrophages and monocytes, with reduced MCP-1 and IL-6 levels. Compared to ovx, blood leukocyte numbers increased already 1h after i.p challenge in ovx+E2 mice., Conclusion: Our findings suggest that ovarian hormones and estradiol can adjust the acute innate immune reaction by regulating cell recruitment to inflammatory sites, diversify the responding cell population, and at the same time down-regulate production of certain pro-inflammatory cytokines. Our results also suggest a faster responding immune system after E2. Our results bring further information into the intricate relationship between inflammation and sex steroids., (Copyright © 2017 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Women are more prone to develop rheumatoid arthritis, with peak incidence occurring around menopause. Estrogen has major effects on the immune system and is protective against arthritis. We have previously shown that treatment with estrogen inhibits inflammation and joint destruction in murine models of arthritis, although the mechanisms involved remain unclear. Fibroblastic reticular cells (FRCs) are specialized stromal cells that generate the three‐dimensional structure of lymph nodes (LNs). FRCs are vital for coordinating immune responses from within LNs and are characterized by the expression of the chemokine CCL19, which attracts immune cells. The aim of this study was to determine whether the influence of estrogen on innate and adaptive immune cells in arthritis is mediated by estrogen signaling in FRCs. Conditional knockout mice lacking estrogen receptor α (ERα) in CCL19‐expressing cells (Ccl19‐CreERαfl/fl) were generated and tested. Ccl19‐CreERαfl/fl mice and littermate controls were ovariectomized, treated with vehicle or estradiol and subjected to the 28‐day‐long antigen‐induced arthritis model to enable analyses of differentiated T‐ and B‐cell populations and innate cells in LNs by flow cytometry. The results reveal that while the response to estradiol treatment in numbers of FRCs per LN is significantly reduced in mice lacking ERα in FRCs, estrogen does not inhibit joint inflammation or markedly affect immune responses in this arthritis model. Thus, this study validates the Ccl19‐CreERαfl/fl strain for studying estrogen signaling in FRCs within inflammatory diseases, although the chosen arthritis model is deemed unsuitable for addressing this question. [ABSTRACT FROM AUTHOR]

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease that is more common in women than in men. The peak incidence in females coincides with menopause when the ovarian production of sex hormones drops markedly. RA is characterized by skeletal manifestations where production of pro-inflammatory mediators, connected to the inflammation in the joint, leads to bone loss. Animal studies have revealed distinct beneficial effects of estrogens on arthritis, and a positive effect of hormone replacement therapy has been reported in women with postmenopausal RA. This review will focus on the influence of female sex hormones in the pathogenesis and progression of RA. [Copyright &y& Elsevier]

The article presents a study to investigate the influence of galectin 3 deficiency in a murine model of arthritis. Wild-type (WT) and galectin 3–deficient (galectin 3&sup–/–;) mice were subjected to antigen-induced arthritis (AIA), and the concentration of serum cytokines, antigen-specific antibodies and cellular IL-17 responses were examined. Galectin 3&sup–/–; mice showed a relatively greater suppression in joint inflammation and bone erosion, thereby suggesting that galectin 3 plays a pathogenic role in the development and progression of AIA.

Abstract: 2-methoxyestradiol (2me2), a metabolite of 17β-estradiol (E2), has been tested in phase II clinical cancer trials and models of inflammation. Its effects are only partly clarified. We investigated the effects of 2me2 on the immune system, using ovariectomized or sham-operated mice treated with a high and a low dose of 2me2 (2me2H and 2me2L), E2 or vehicle. We investigated antagonism of tissue proliferation and estrogen response element (ERE) activation. Established immunomodulation by E2 was reproduced. 2me2L increased NK and T-cells from bone marrow, spleen and liver. Both 2me2H and E2 induced uterus proliferation in ovariectomized mice, but no antagonistic effects on uteri growth were seen in intact animals. Both E2 and 2me2H activated EREs. Immunomodulation by 2me2 is tissue-, and concentration dependent. E2 regulated the immune system more potently. The higher dose of 2me2 resulted in E2 like effects, important to consider when developing 2me2 as a drug. [Copyright &y& Elsevier]

Lasofoxifene (las) and bazedoxifene (bza) are third generation selective estrogen receptor modulators (SERMs) with minimal estrogenic side effects, approved for treatment of postmenopausal osteoporosis. T cells are involved in the pathology of postmenopausal osteoporosis and previous studies have established an important role for 17β-estradiol (E2) in T cell development and function. E2 causes a drastic thymic atrophy, alters the composition of thymic T cell populations, and inhibits T cell dependent inflammation. In contrast, the second generation SERM raloxifene (ral) lacks these properties. Although las and bza are drugs approved for treatment of postmenopausal bone loss, it is of importance to study their effects on other biological aspects in order to extend the potential use of these compounds. Therefore, the aim of this study was to investigate if treatment with las and bza affects T lymphopoiesis and T cell dependent inflammation. C57Bl6 mice were ovariectomized (ovx) and treated with vehicle, E2, ral, las or bza. As expected, E2 reduced both thymus weight and decreased the proportion of early T cell progenitors while increasing more mature T cell populations in the thymus. E2 also suppressed the T cell dependent delayed-type hypersensitivity (DTH) reaction to oxazolone (OXA). Ral and las, but not bza, decreased thymus weight, while none of the SERMs had any effects on T cell populations in the thymus or on inflammation in DTH. In conclusion, this study shows that treatment with las or bza does not affect T lymphopoiesis or T cell dependent inflammation. [ABSTRACT FROM AUTHOR]