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Estrogen receptor alpha promotes lupus in (NZB×NZW)F1 mice in a B cell intrinsic manner.

ABSTRACT: Lupus is a systemic autoimmune disease characterized by the production of autoreactive antibodies against nuclear antigens. Women are disproportionately affected by lupus, and this sex bias is thought to be due, in large part, to the ability of estrogens to promote lupus pathogenesis. Previously, we have shown that global deletion of estrogen receptor alpha (ER?) significantly attenuated loss of tolerance, immune cell activation, autoantibody production, and the development of lupus nephritis. Here we show that targeted deletion of ER? specifically in B cells retards production of pathogenic autoantibodies and the development of nephritis in lupus-prone (NZB×NZW)F1 mice. Furthermore, we observed that ER? deletion in B cells was associated with decreased B cell activation in young, pre-autoimmune (NZB×NZW)F1 females. Altogether, these data suggest that ER? acts in a B cell-intrinsic manner to control B cell activation, autoantibody production, and lupus nephritis.

SUBMITTER: Tabor DE

PROVIDER: S-EPMC5316311 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Estrogen receptor alpha promotes lupus in (NZB×NZW)F1 mice in a B cell intrinsic manner.

Tabor Dana E DE Gould Karen A KA

Clinical immunology (Orlando, Fla.) 20161029

Lupus is a systemic autoimmune disease characterized by the production of autoreactive antibodies against nuclear antigens. Women are disproportionately affected by lupus, and this sex bias is thought to be due, in large part, to the ability of estrogens to promote lupus pathogenesis. Previously, we have shown that global deletion of estrogen receptor alpha (ERα) significantly attenuated loss of tolerance, immune cell activation, autoantibody production, and the development of lupus nephritis. H ...[more]

PMID: 27989899

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Project description:Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase mediating trimethylation of H3K27, which represses gene expression and is critical to immune regulation. Inhibition of EZH2 is proved to have the potential of treating many diseases. However, whether inhibition of EZH2 affects type I interferon (IFN-I) signaling pathway, the abnormality of which is an important pathogenic mechanism for SLE, is still elusive. Here, we report, unexpectedly, a positive regulatory function of EZH2 in IFN-I signaling pathway, which contributes to the overactivation of IFN-I signaling pathway in SLE. We show that the expression of EZH2 was upregulated and positively correlated with the overexpression of interferon stimulated genes (ISGs) in both peripheral blood mononuclear cells and renal tissues of SLE patients. In vitro inhibition of EZH2 by either siRNAs or chemical inhibitors reduced the phosphorylation of STAT1 and the induction of ISGs stimulated by IFN-I. Additionally, inhibition of EZH2 interfered with the in vivo and ex vivo activation of IFN-I signaling pathway elicited by intravenous injection of adenovirus vector expressing mouse IFN-α5 and exogeneous stimulation with IFN-α, respectively. We evaluated the therapeutic effects of EZH2 inhibitor in NZB/NZW F1 mice which depend on IFN-I signaling pathway for the lupus-like disease development. Administration of EZH2 inhibitor prolonged the survival, reduced the levels of anti-dsDNA autoantibodies, and improved lupus nephritis of the mice. What's more, EZH2 inhibitor attenuated the expression of ISGs in the kidneys of these mice. In summary, we show that excessive EZH2 contributes to the overactivation of IFN-I signaling pathway in SLE. EZH2 inhibitor has the potential to inhibit IFN-I signaling pathway and alleviate lupus nephritis. Additionally, diverse disease driving pathways exist among systemic lupus erythematosus (SLE) patient, and even in the same patients. Common regulators of different pathogenic pathways can be multivalent therapeutic targets. Together with previous studies showing EZH2 is involved in T-cell and B-cell mediated immune responses, EZH2 could be a potent multivalent therapeutic target for SLE.

Dataset Information

Estrogen receptor alpha promotes lupus in (NZB×NZW)F1 mice in a B cell intrinsic manner.

Publications

Estrogen receptor alpha promotes lupus in (NZB×NZW)F1 mice in a B cell intrinsic manner.

Similar Datasets

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