Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains

Abstract

It has been proposed that homeostatic levels of estrogen can enhance female susceptibility to autoimmunity, whereas the heightened levels of estrogen associated with pregnancy are protective. This hypothesis was tested using the mouse model of experimental autoimmune encephalomyelitis (EAE). Diestrus (<100 pg/ml in serum) levels of 17β-estradiol were found to significantly reduce the clinical manifestations of active EAE in both male and female mice. Estriol was also effective but at doses below those previously established for pregnancy. The reduction in disease severity was accompanied by a coincident reduction in the number and size of inflammatory foci in the CNS of estrogen (17β-estradiol or estriol)-treated mice. Recipients of encephalitogenic T cells from low-dose estrogen-treated mice developed less severe paralysis than mice receiving T cells from placebo-treated mice. A modest shift in Th1/Th2 balance suggested that low dose estrogen therapy could bias the immune reaction toward a protective anti-inflammatory cytokine response. However, estrogen treatment at the onset of active EAE failed to reduce disease severity, a result that is consistent with the hypothesis that naive cells are more sensitive to sex hormones than differentiated effector cells. These data suggest that treatment with low doses of estrogen can reduce the capacity of developing myelin-reactive T cells to initiate disease and challenges the idea that increased susceptibility to autoimmunity in females is dependent on homeostatic levels of estrogen.

T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

“…27 The protective effect of E2 was associated with diminished migration of encephalitogenic T cells into the CNS and effects on dendritic cells and macrophages. 28,29 Recently, we also showed using knockout mice that Esr1 is required for the protective effect of E2 on EAE.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Physiological or pharmacological fluctuations in estrogen levels have been recognised since a long time to play a regulatory role in EAE ( [13,108,111,119,150]). Oral administration of low doses of estrogenic hormones, 17beta-estradiol and ethinyl estradiol, drastically reduce the severity of EAE and this effect was reconciled with a decrease in the production of inflammatory Th1 cytokines (such as inteferon-c (IFN-c), Tumor Necrosis Factor-a (TNF-a), Interleukin (IL)-1 and IL-6), chemokines/receptors, while increasing the expression of anti-inflammatory Th2 cytokines (including IL-4, IL-5 and Transforming Growth factor-b3 (TGF-b3)) ( [13,108,150,222]).…”

“…Oral administration of low doses of estrogenic hormones, 17beta-estradiol and ethinyl estradiol, drastically reduce the severity of EAE and this effect was reconciled with a decrease in the production of inflammatory Th1 cytokines (such as inteferon-c (IFN-c), Tumor Necrosis Factor-a (TNF-a), Interleukin (IL)-1 and IL-6), chemokines/receptors, while increasing the expression of anti-inflammatory Th2 cytokines (including IL-4, IL-5 and Transforming Growth factor-b3 (TGF-b3)) ( [13,108,150,222]). This observation together with the fact that no infiltrating lymphocytes were found in the hormone-treated animals, led to the conclusion that estrogens protects mice from EAE by inhibiting the recruitment of T cells and macrophages into the CNS.…”

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

“…After puberty, MS occurs two times more frequently in the female than the male (Czlonkowska et al, 2005;Hughes, 2004), but pregnancy has a protective effect (Confavreux et al, 1998). Treatment of MS in humans and experimental allergic encephalomyelitis (EAE) in mice by estrogens ameliorates these diseases (Bebo et al, 2001;Morales et al, 2006;Soldan et al, 2003). An immunomodulatory effect had been suspected (Lang, 2004), but it has recently been shown that in EAE, estradiol exerts its ameliorating effect via ERa receptors in CNS-resident cells, not in lymphocytes (Garidou et al, 2004).…”