EXPLORING THE ROLE OF ESTROGEN RECEPTOR ALPHA VARIANTS IN TLR7-INDUCED LUPUS PATHOGENESIS
Bibliographic record
Abstract
PV117 / #372 Poster Topic: AS14 - Innate Immunity Background/Purpose Lupus is a classical autoimmune disease affecting mainly women of reproductive age, which has led to investigations into the role of sex hormones and their receptors in its pathogenesis. Our previous research has shown that a functional knockout of estrogen receptor alpha (expressing ERα short, similar to endogenous ERα46), but not complete ERα deletion, protected lupus-prone mice from disease development, suggesting complex effects of ERα variants on lupus pathogenesis. This study aims to investigate the role of 2 ERα variants, the classic full-length ERα66 and a short variant ERα46, in modulating the inflammatory response to Toll-like receptor 7 (TLR7) stimulation, which is involved in the pathogenesis of lupus. Methods Raw 264.7 cells (a mouse macrophage cell line) were transfected with a plasmid containing ERα66 or ERα46, with an empty plasmid as a control. After 24h, cells were treated with 0.2 mM loxoribine (Lox), a TLR7 agonist, or an equal volume of DMSO (vehicle) for 1h or 18h. The expression of ERα66 and ERα46 was validated by RT-qPCR and western blot. RNA levels of proinflammatory cytokines (IL-6, IL-1β, and TNF-α, among others) were then assessed. Results Compared to plasmid control (pc), where no endogenous expression of ERα66 or ERα46 was detected by western blot, Raw 264.7 cells transfected with ERα66 or ERα46 plasmids successfully overexpressed ERα66 or ERα46 protein. RT-qPCR showed consistent results: ERα mRNA was only increased in cells overexpressing ERα66 using primers to exon 1-2 (only exists in ERα66), and in parallel experiments, ERα mRNA level was increased in both ERα66 and ERα46-over-expressing cells when using primers to exon 4-5 (shared by both). Unexpectedly, our pilot data showed that both ERα46 and ERα66 overexpression promoted IL-6, IL-1β, and TNF-α by macrophages in response to TLR7 stimulation, contrary to our hypothesis that ERα46 might antagonize the proinflammatory influence of ERα66 in lupus. Conclusions Two main ERα variants, ERα66 and ERα46, both promote the activation and inflammatory response of macrophages in the setting of low/no estrogen. Since our previous in vivo studies demonstrated a requirement for estrogen in the protective effect of ERα46 in disease expression, further studies are needed to systemically elucidate the respective roles of ERα66 and ERα46 in lupus pathogenesis in the setting of estrogen.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 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".