Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

Abstract

Estrogen is a neuro-protective hormone in various central nervous system (CNS) disorders. The present study evaluated the role of estrogen during experimental autoimmune encephalomyelitis (EAE) at doses selected to mimic any suppressive potential from the hormone during pregnancy. Here, mice were ovariectomized and then 2 weeks later treated with MOG antigen to induce EAE. Concurrently, mice then received (subcutaneously) an implanted pellet to deliver varying estrogen amounts over a 21-day period. Clinical scores and other parameters were monitored daily for the 21 days. At the end of the period, brain/spinal cord histology was performed to measure lymphocyte infiltration; T-cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed using real-time PCR; T-cell differentiation was evaluated via flow cytometry. The results demonstrated that estrogen inhibited development of EAE. Histological studies revealed limited leukocyte infiltration into the CNS. High and medium dose of estrogen increased T H 2 and T reg cell production of interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-b, but concurrently resulted in a significant reduction in production of interferon (IFN)-c, IL-17, and IL-6. Flow cytometry revealed there were also significant decreases in the percentages of T H 1 and T H 17 cells, as well as significant increase in percentages of T reg and T H 2 cells in the spleen and lymph nodes. Real-time PCR results indicated that high-and medium-dose estrogen treatments reduced T-bet and ROR-ct factor expression, but enhanced Foxp3 and GATA3 expression. Collectively, these results demonstrated that a medium dose of estrogen -similar to a pregnancy level of estrogen -could potentially reduce the incidence and severity of autoimmune EAE and possibly other autoimmune pathologies.ARTICLE HISTORY

The Roles of Sex Hormones in the Course of Atopic Dermatitis

“…The immunomodulatory effects of E2 are mediated mainly by intracellular estrogen receptor α (ERα) and ERβ or structurally unrelated membrane G-protein-coupled estrogen receptor 1. E2 promotes Th2 activity [26,32]: E2 at pregnancy levels of concentration enhanced the expression of GATA binding protein 3 (GATA3) and IL-4 in ovariectomized experimental autoimmune encephalomyelitis (EAE) model mice [23]. E2 also enhanced IgE production in mouse splenocytes [27].…”

Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen

“…This suggests other factors in addition to E2 are necessary to increase the frequency of CD4 Treg cells and these are absent in OVX female mice. One reason for the difference in the previous findings in OVX female mice is the time when E2 was administered (eg, within 30 min after the induction of EAE compared (Haghmorad et al 2016) to 7 days prior to the induction of EAE). Another subset of Treg cells are CD8 Treg cells (CD8 + CD122 + ) which are protective after stroke (Bodhankar et al 2015a).…”

“…Other studies have shown estrogen increases CD4 Treg cells (CD4 + CD25 + FoxP3 + ) in intact female mice during EAE (Polanczyk et al 2005). Even OVX female mice treated with E2 after the induction of EAE demonstrated some protection from EAE and an increased frequency of CD4 Treg cells (Haghmorad et al 2016). Interestingly, intact female and male mice had a significant increase in the frequency of CD4 Treg cells in E2 pretreated mice compared to sham pretreatment, but OVX female mice had a significant decrease in the frequency of CD4 Treg cells in E2 pretreated mice compared to sham pretreated mice.…”

Amelioration of regulatory T cells by Lactobacillus delbrueckii and Lactobacillus rhamnosus in pristane‐induced lupus mice model

“…The splenocytes were separated using needle perfusion method. The red blood cells were then removed using lyses buffer (Tris-NH 4 Cl) and (Haghmorad et al, 2016). β2-Microglobulin (β2m) was used as a housekeeping gene for the normalization of the C t values for the genes of interest.…”