MEMBRANE-LOCALIZED ESTROGEN RECEPTOR ALPHA (ERΑ) IS REQUIRED FOR BOTH NORMAL AND TLR7-INDUCED DEVELOPMENT OF CD11B+LY6C+ INFLAMMATORY MONOCYTES
Bibliographic record
Abstract
PV115 / #373 Poster Topic: AS14 - Innate Immunity Background/Purpose Lupus is a disease that disproportionately affects females. We previously showed that selective expression of an ERα short variant in lupus-prone mice resulted in significantly reduced renal disease and increased survival. The mechanism of this protective effect, which required estradiol, is not known but may relate to the role of ERα in innate immune cells since dendritic cell subsets were significantly impacted. Methods We investigated the immunophenotype of mice expressing ERα that is selectively targeted to the cytosolic membrane (MOER) vs. nuclear-restricted ERα (NOER) to further explore the role of ERα in innate immune cells from these mutant mice (on a C57/B6j background). We subsequently stimulated these mice in vivo with a TLR7 agonist (topical R848) for 4 weeks and analyzed ex vivo bone marrow and spleen cell populations as well as manifestations of lupus-like disease (ex. autoantibodies, splenomegaly, blood counts, kidney function). Results Total BM cells were surprisingly reduced in NOER mice when compared to MOER in ovary intact animals (p=0.037). A significant decrease was also observed in CD11b+ cells from NOER BM and a trend toward decreased CD11c+ and MHCII+ cells, but not CD19+ cells, suggesting that membrane ERα rather than nuclear ERα is required for normal development of CD11b+ cells and perhaps other myeloid cells, but is not required for B cell development. When assessing spleen, there was a significant increase in CD11b+Ly6C+ cells (inflammatory monocytes) in MOER mice. NOER mice had reduced numbers of CD11b+Ly6C+ cells, suggesting an inability to mount a robust response to TLR7 stimulation when compared to WT and MOER mice. In BM, Ly6C+ and Ly6C+CD11b+ cells had similar trends with statistically significant enrichment from MOER mice regardless of treatment status. R848-treated MOER mice also had a significant leukocytosis (increased WBCs, p=0.0077) and increased blood urea nitrogen (BUN) reflecting an early change in renal function compared to NOER mice (p=0.002), suggesting that membrane ERα mediates these physiologic effects. Renal pathology and immunohistochemistry demonstrated significantly increased glomerular IgG deposition in R848-treated mice, which was also mildly increased in TLR7-stimulated MOER mice. Conclusions These findings suggest nuanced interactions between estradiol, ERα, and immune regulation. The study underscores the pivotal roles played by both nuclear and membrane ERα in both immune cell development and function. Further investigations are warranted to elucidate the precise mechanisms through which distinct ERα isoforms and their subcellular localization exert influence on immune responses.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".