Background/Purpose: Systemic lupus erythematosus is a disease that disproportionately affects females. The mechanisms underlying the female predominance in this disease are largely unknown. We previously showed that estrogen receptor alpha (ERα) deficiency resulted in significantly reduced renal disease and increased survival in murine lupus. More recently we showed a role for ERα in TLR induction of the IL-23/IL-17 inflammatory pathway. TLR7 and TLR9 agonists induced significant increases in IL-1β and IL-23 expression in dendritic cells derived from ERα+/+, but not ERα-/- mice. Additionally, TLR7 and TLR9 stimulation upregulated IL-23R, which is critical for the stabilization of the Th17 cell phenotype, but this effect could not be demonstrated in the absence of ERα. We hypothesized that the capacity to expand/stabilize Th17 cells is partially regulated by ERα. 

Methods: NZM2410 lupus-prone mice (n=19) were sacrificed at 17-19wks and spleens were harvested. T cells were isolated and analyzed prior to and after 4-5d Th17 polarizing conditions (stimulated with CD3/CD28 beads, +TGFβ, +IL-6, +anti-IFNγ, +anti-IL-4; +IL-23 on d3). Flow cytometry, ELISA and RT-PCR were used to evaluate IL-17/CD4 positivity, and IL-21, ICOS, IL-23R message levels, respectively. 

Results: Consistent with previous experiments that demonstrated reduced IL-17-producing ex vivo spleen cells from ERα deficient mice, we now show that T cells isolated from NZM2410 ERα-/- mice also produce less IL-17 and have reduced IL-21, ICOS, and IL23R mRNA levels compared with WT NZM2410.  In addition, under Th17 polarizing conditions, fewer Th17 (IL17+/CD4+) cells were attained from NZM2410 ERα-/- mice. 

Conclusion: T cells from lupus-prone ERα-/- mice express less IL-17 and other markers of Th17 development and stabilization. Taken together, our previous and current data suggest that ERα impacts the IL-23/IL-17 inflammatory pathway. A reduction in Th17 cells may partially explain the decrease in inflammatory renal damage and increased survival in ERα deficient animals.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/estrogen-receptor-alpha-impacts-th17-expansion-in-murine-lupus/