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Novel mechanism for estrogen receptor alpha modulation of murine lupus.

ABSTRACT: Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ER?) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ER? KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ER? KO constructs. Our objective was to compare a complete KO of ER? vs. the original functional KO of ER? (expressing a short ER?) on disease expression and immune phenotype, while controlling sex hormone levels. We studied female lupus prone NZM2410 WT and ER? mutant mice. All mice (n = 44) were ovariectomized (OVX) for hormonal control. Groups of each genotype were estrogen (E2)-repleted after OVX. We found that OVXed NZM mice expressing the truncated ER? (ER? short) had significantly reduced nephritis and prolonged survival compared to both wildtype and the complete ER?KO (ER? null) mice, but surprisingly only if E2-repleted. ER? null mice were not protected regardless of E2 status. We observed significant differences in splenic B cells and dendritic cells and a decrease in cDC2 (CD11b+CD8-) dendritic cells, without a concomitant decrease in cDC1 (CD11b-CD8a+) cells comparing ER? short to ER? null or WT mice. Our data support a protective role for the ER? short protein. ER? short is similar to an endogenously expressed ER? variant (ER?46). Modulating its expression/activity represents a potential approach for treating female-predominant autoimmune diseases.

SUBMITTER: Cunningham MA

PROVIDER: S-EPMC6351212 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Novel mechanism for estrogen receptor alpha modulation of murine lupus.

Cunningham Melissa A MA Richard Mara Lennard ML Wirth Jena R JR Scott Jennifer L JL Eudaly Jackie J Ruiz Phil P Gilkeson Gary S GS

Journal of autoimmunity 20181108

Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERα) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ERα KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ERα KO constructs. Our objective was to compare a complete KO of ERα vs. the original functional KO of ERα (expressing a ...[more]

PMID: 30416032

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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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Novel mechanism for estrogen receptor alpha modulation of murine lupus.

Publications

Novel mechanism for estrogen receptor alpha modulation of murine lupus.

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