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Complete knockout of estrogen receptor alpha is not directly protective in murine lupus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease that disproportionately affects women. Despite a known role for hormonal factors impacting autoimmunity and disease pathogenesis, the specific mechanisms of action remain poorly understood. Our laboratory previously backcrossed "estrogen receptor alpha knockout (ER?KO)" mice onto the NZM2410 lupus prone background to generate NZM/ER?KO mice. This original ER?KO mouse, developed in the mid-1990s and utilized in hundreds of published studies, is not in fact ER? null. They express an N-terminally truncated ER?, and are considered a functional KO. They have physiologic deficiencies including infertility due to disruption of a critical activation domain (AF-1) at the N terminus of ER?, required for most classic estrogen (E2) actions. We demonstrated that female NZM/ER?KO mice had significantly less renal disease and significantly prolonged survival compared to WT littermates despite similar serum levels of autoantibodies and glomerular immune complex deposition. Herein, we present results of experiments using a lupus prone true ER?-/- mice (deletional KO mice on the NZM2410 background), surprisingly finding that these animals were not protected if they were ovariectomized, suggesting that another hormonal component confers protection, possibly testosterone, rather than the absence of the full-length ER?.

SUBMITTER: Scott JL

PROVIDER: S-EPMC6261466 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Complete knockout of estrogen receptor alpha is not directly protective in murine lupus.

Scott Jennifer L JL Wirth Jena R JR Eudaly Jackie J Ruiz Phil P Cunningham Melissa A MA

Clinical immunology (Orlando, Fla.) 20170816

Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease that disproportionately affects women. Despite a known role for hormonal factors impacting autoimmunity and disease pathogenesis, the specific mechanisms of action remain poorly understood. Our laboratory previously backcrossed "estrogen receptor alpha knockout (ERαKO)" mice onto the NZM2410 lupus prone background to generate NZM/ERαKO mice. This original ERαKO mouse, developed in the mid-1990s and utilized ...[more]

PMID: 28822833

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Project description:BackgroundOne of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ER? deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ER? deficiency would be similarly protective in the brain, and that ER? may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice.MethodsMRL/lpr ER?+/+ and ER?KO mice (n?=?46) were ovariectomized, received 17?-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting.ResultsMRL/lpr ER?KO mice (n?=?21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n?=?25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ER?KO mice. There were significant differences in NOR testing, particularly total exploration time, with ER? deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ER?KO mice, as evidenced by immunohistochemietry (IHC).ConclusionER? deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ER?KO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.

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Complete knockout of estrogen receptor alpha is not directly protective in murine lupus.

Publications

Complete knockout of estrogen receptor alpha is not directly protective in murine lupus.

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