Estrogen Receptor α Signaling in T Lymphocytes Is Required for Estradiol-Mediated Inhibition of Th1 and Th17 Cell Differentiation and Protection against Experimental Autoimmune Encephalomyelitis

Abstract

Estrogen treatment exerts a protective effect on experimental autoimmune encephalomyelitis (EAE) and is under clinical trial for multiple sclerosis therapy. Estrogens have been suspected to protect from CNS autoimmunity through their capacity to exert anti-inflammatory as well as neuroprotective effects. Despite the obvious impacts of estrogens on the pathophysiology of multiple sclerosis and EAE, the dominant cellular target that orchestrates the anti-inflammatory effect of 17β-estradiol (E2) in EAE is still ill defined. Using conditional estrogen receptor (ER) α-deficient mice and bone marrow chimera experiments, we show that expression of ERα is critical in hematopoietic cells but not in endothelial ones to mediate the E2 inhibitory effect on Th1 and Th17 cell priming, resulting in EAE protection. Furthermore, using newly created cell type-specific ERα-deficient mice, we demonstrate that ERα is required in T lymphocytes, but neither in macrophages nor dendritic cells, for E2-mediated inhibition of Th1/Th17 cell differentiation and protection from EAE. Lastly, in absence of ERα in host nonhematopoietic tissues, we further show that ERα signaling in T cells is necessary and sufficient to mediate the inhibitory effect of E2 on EAE development. These data uncover T lymphocytes as a major and nonredundant cellular target responsible for the anti-inflammatory effects of E2 in Th17 cell-driven CNS autoimmunity.

Osteoimmunology and Its Implications for Transplantation

“…The differentiation of the Th17 subset of CD4þ cells is inhibited by estrogen via a direct effect mediated by ERa (42). The specific contribution of Th17 in ovx induced bone loss remains controversial as one study reported that IL-17R null mice are more susceptible to ovx induced bone loss than controls (43), while another group found mice lacking IL-17R and mice treated with anti IL-17 antibody to be protected against ovx induced bone loss (44).…”

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

“…Estrogen effects are mediated by estrogen receptors (ERs) ERa and ERb, which function as ligand-induced transcription factors (3). This regulatory action of estrogens on immune responses and autoimmunity are thought to be due to a direct action on immunocompetent cells of the innate and adaptive immune systems (4), which have been recently shown to functionally express ERs, particularly ERa (5)(6)(7)(8)(9)(10)(11). Alternatively, estrogens, through their ERs, may act on precursor cells to regulate the differentiation and functions of lymphoid and myeloid cells (12)(13)(14)(15)(16)(17)(18).…”

Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice

“…Estrogeninduced EAE protection is mediated by upregulated PD-1 expression within the Treg-cell compartment, which reduces peripheral IL-17 production (9). Lelu et al demonstrated that hematopoietic cell ERα expression is critical for mediating E2s inhibitory effect on Th1 and Th17 cell priming, which results in EAE protection (8). However, to our knowledge, there have been no publications regarding the effect of ERα on IL-23 in EAE.…”

“…Secondly, certain studies have reported estrogen-mediated protection against EAE in regulatory B cells and the mediation of MMP-9 activity through ERα (10,23). Thirdly, Lelu et al demonstrated that ERα expression is critical in hematopoietic, but not endothelial cells; it mediates the estrogen inhibitory effect on Th1 and Th17 cell priming, which protects against EAE (8). Finally, reactive astrocytes are a target of the inhibitory action of nuclear ERα on chemokine expression; this observation suggests that targeting astrocytic nuclear factor-κB may be a useful therapeutic goal (15,24).…”

“…Clinical studies have indicated that oral estrogen administration exerts immunoregulatory effects and reduces the number and size of gadolinium-enhancing lesions in relapsing-remitting MS patients, suggesting that estrogen is an effective drug for MS therapy (6,7). Certain studies have reported that estriol exerts anti-inflammatory effects, such as inhibiting Th1 and Th17 cell priming (8,9), regulatory B cells (10) and T cells (11), as well as inhibiting matrix metalloproteinase-9 (MMP-9) activity (12). Other studies have demonstrated that estriol decreases gray matter atrophy (13) and reduces inappropriate excitatory synaptic transmission and other neuropathological hippocampal changes during EAE (14).…”