MEMBRANE-LOCALIZED ESTROGEN RECEPTOR ALPHA (ERΑ) IS REQUIRED FOR BOTH NORMAL AND TLR7-INDUCED DEVELOPMENT OF CD11B+LY6C+ INFLAMMATORY MONOCYTES
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».