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. 2026 Apr 29;8(5):e90031. doi: 10.1002/acr2.90031

The ERβ Agonist, OSU‐ERβ‐012, Mitigates Inflammation in a Chimeric Model of Systemic Lupus Erythematosus

Braden Zeno 1,[Link], Shane Bruckner 1,[Link], Hongyu Yuan 1,[Link], Morgan Stahl 1,[Link], Timothy Alexandrov 1,[Link], Kyle Jablonski 1,[Link], Judith Lin 1,[Link], Nicholas A Young 1,[Link], Wael N Jarjour 1,✉
PMCID: PMC13129409  PMID: 42057532

Abstract

Objective

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ damage, affecting women between the ages of 15 and 45 years at a 9:1 rate as compared to men. The etiology of SLE is complex and elusive; however, the susceptibility of women during the years in which estrogen levels are at their highest suggests a significant contribution to the development of SLE. Previously, our group and others have shown that estrogen receptor α (ERα) carrying immune cells are mediators of the proinflammatory effects of estrogen as compared to cells that lack this receptor. ERβ, the other estrogen responsive transcription factor, has been postulated to have an antagonistic effect to ERα, which mediates the anti‐inflammatory effects of estrogen.

Methods

In the pursuit of a drug that is tailored to have a favorable selective estrogenic effect, The Ohio State University Drug Development Institute discovered a novel carborane‐based selective ER modulator, OSU‐ERβ‐012. This ERβ agonist exhibits potent binding of human ERβ (Ki = 2.0 nM) and functional selectivity for ERβ over ERα of at least 200‐fold. We tested the effectiveness of OSU‐ERβ‐012 in treating lupus‐humanized NSG mice by examining serum for the presence of inflammatory cytokines and histopathology of hearts and kidneys.

Results

The humanized mice exhibited increased expression of inflammatory cytokines, pericarditis, and increased glomerular size, which were all mitigated by the treatment with OSU‐ERβ‐012.

Conclusion

OSU‐ERβ‐012 is an effective therapeutic in this NSG mouse model with humanized SLE because it inhibits the proinflammatory renal and cardiac phenotype.

INTRODUCTION

Systemic lupus erythematosus (SLE) is a complex, multiorgan autoimmune disease that preferentially afflicts women with a ratio of 9:1 during childbearing years. 1 The etiology of SLE remains elusive; however, genetic, environmental, and hormonal factors all have been shown as contributors to the pathogenesis of the disease. 2 Although the cause may be multifactorial, it is clear that SLE has a strong predilection for females during their reproductive years when estrogen levels are at their highest, and this striking difference is diminished before the onset of puberty and after menopause when estrogen levels are reduced. 3 During this period of high circulating estrogen, it has been well described that women mount stronger innate and adaptive immune responses than men, providing a survival advantage against infectious diseases but also an increased likelihood of developing autoimmunity. 4 Studies in both animal models and humans have demonstrated an important role of estrogen in the female predominance observed in SLE; however, the specific effects of estrogen on lupus‐associated cardiovascular and renal manifestations remain unclear.

The pleiotropic effects of estrogen on the immune system are mediated through the transcription factors estrogen receptor α (ERα) and estrogen receptor β (ERβ), or the cell surface G protein–coupled estrogen receptor 1 (GPER1). 5 ERα has been studied extensively in the context of SLE; however, ERβ and GPER1 have received much less attention. ERα and ERβ form both homodimers and heterodimers, and they are expressed in many cells of the immune system including T cells, B cells, monocytes, and dendritic cells. 6 , 7 , 8 ERα and ERβ regulate gene transcription, having both overlapping and distinct target genes, whereas some reports suggest that they can function antagonistically. 9 Studies about the specific roles of ERα and ERβ in modulating the effects of estrogen on SLE have suggested a proinflammatory role for ERα contributing to disease pathogenesis. 10 , 11 , 12 , 13 Interestingly, deletion of ERα in mice prone to lupus led to reduced disease, whereas ERβ deletion had no effect, suggesting a disease‐promoting effect of ERα, whereas the role of ERβ remains ambiguous. 14 , 15

If susceptibility of SLE is increased during the years in which women have the highest levels of estrogen, and estrogen receptors are expressed in immune cells that are thought to mediate the lupus phenotype, then it stands that the differential effects of estrogen receptorss may be a significant contributor to this debilitating disease phenotype. In fact, it has been shown that ERβ expression is negatively correlated with a disease activity in premenopausal female patients with SLE, suggesting a possible role for differential expression in the progression of the disease. 16 Additionally, antagonism of ERβ exacerbates SLE in a mouse model of the disease. 17 Therefore, we hypothesized that the treatment with a specific ERβ agonist may potentially be an effective therapeutic in the treatment of SLE. Here, we used a highly selective novel carborane‐based ERβ agonist, OSU‐ERβ‐012, that was developed by the Drug Development Institute at The Ohio State University. 18 , 19 We examined whether this ERβ agonist could ameliorate the disease phenotype in a humanized mouse model of SLE, and we report that this compound is very effective in reducing pericarditis, myocarditis, proinflammatory cytokines, and kidney pathology in this model of lupus.

MATERIALS AND METHODS

Human samples

Patients with lupus were recruited from The Ohio State University Wexner Medical Center (OSUWMC) Lupus Clinic and met the revised criteria of the American College of Rheumatology for SLE. 20 All participants in the study provided written informed consent, and the research was conducted under an Institutional Review Board–approved protocol at OSUWMC in compliance with the ethical guidelines of the 1975 Declaration of Helsinki.

Mice

NOD.Cg‐Prkdcscid IL2rgtm1Wjl or SzJ (NSG, JAX stock 005557) were procured from The Jackson Laboratory and housed in NexGen individually ventilated cage rack caging system on corncob bedding with a compressed cotton nestlet. Cages were autoclaved before use; irradiated feed (Envigo Teklad 7912) was provided ad libitum, and reverse osmosis chlorinated water was provided via automatic water valves. Cages were changed every two weeks in a biosafety cabinet, and light was provided on a 12:12 cycle. Inhaled isoflurane at 1% to 5% in 100% oxygen was used for anesthesia as needed. All animal protocols were approved by the Institutional Animal Care and Use Committee through University Laboratory Animal Resources at OSUWMC.

Lupus‐humanized NSG mouse model

For each experiment, at least 1.5 × 108 peripheral blood mononuclear cells (PBMCs) from whole blood of patients with active SLE were isolated from a single patient and then 1 × 107 cells were adoptively transferred via intraperitoneal (IP) injection into 15 female NSG mice, as previously described. 12 The injected PBMCs were allowed to expand in vivo for one week to ensure that the lupus disease phenotype was well established before the mice began treatments. Subsequently, the mice were divided into three cohorts of five mice each, which were treated with either vehicle control (5% DMSO/5% Tween‐20), 5 mg/kg prednisone, or 50 mg/kg OSU‐ERβ‐012 via daily oral gavage for four weeks. One mouse in the group treated with OSU‐ERβ‐012 died due to complications in the gavage process. Blood samples were taken at baseline and three and five weeks, and the serum was isolated and stored at −80°C. At the experimental endpoint, mice were euthanized with CO2, and hearts, serum, and kidneys were harvested and fixed in 10% neutral buffered formalin for 24 hours at 4°C and subsequently buffer exchanged into 70% ethanol for storage at 4°C. We have previously demonstrated that this NSG chimeric mouse model did not display symptoms of graft‐versus‐host disease (GvHD) with transfers of up to 2 × 107 PBMCs for at least a five‐week window, allowing for the evaluation of patient disease‐specific phenotypes. 12 As an additional control for GvHD and to demonstrate that the SLE disease‐specific phenotype only exists in the mice who were SLE humanized in this model, 1 × 107 PBMCs from a healthy donor were adoptively transferred via IP injection into five female NSG mice. Hearts and kidneys from these controls were evaluated by Masson's trichrome and hematoxylin and eosin (H & E; as described below), which showed that the SLE‐specific phenotype (ie, heart and kidney pathology) as well as the GvHD phenotype was absent in these mice (Supplementary Figure 1).

Histology

Histology was performed by HistoWiz Inc (histowiz.com) using a standard operating procedure and fully automated workflow. Samples were processed, embedded in paraffin, and sectioned at 4 μm. After H&E, Masson's trichrome, or immunohistochemistry (IHC) staining, sections were dehydrated and film coverslipped using a TissueTek‐Prisma and Coverslipper (Sakura). IHC antibodies used by Histowiz were antimyeloperoxidase (Histowiz catalog ab9535), anti‐CD3 (Histowiz catalog ab16669), anti‐F4/80 (Histowiz catalog 14‐4801‐82), anti‐CD11b (Histowiz catalog ab2248000), and anti–α‐SMA (Histowiz catalog ab5694). Whole‐slide scanning (40×) was performed on an Aperio AT2 (Leica Biosystems). Subsequently, the digital slide images of the kidneys were analyzed using the QuPath Bioimage Analysis Software, version 0.5.1. 21

Serum cytokine analysis

Serum samples were analyzed for circulating human cytokines using the Mesoscale Diagnostics V‐PLEX Proinflammatory Panel 1 Human Kit in the Analytical and Development Laboratory, Clinical Research Center at OSU, according to manufacturer recommendations and established standard operating procedures.

Statistical analysis

Quantitative data were analyzed with GraphPad Prism version 10.1.0 with one‐way or two‐way analysis of variance and Tukey's post hoc multiple comparison tests (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001).

RESULTS

OSU‐ERβ‐012 ameliorates heart pathology

Survival rates in SLE have significantly improved, yet deaths due to cardiovascular disease (CVD) of patients with lupus have not. 22 CVD accounts for approximately one‐third of deaths of patients with SLE and is the leading cause of lupus death in some cohorts. 23 Cardiac involvement in patients with SLE can negatively impact all components of the cardiovascular system and heart, 24 with pericarditis being the most common cardiac manifestation of SLE. 25

To assess the effect of ERβ agonism on the lupus‐associated cardiac phenotype, a blood sample was obtained from a patient with SLE who was experiencing pericarditis and was used to humanize a cohort of 15 mice, which were then divided into groups of 5 mice each and then treated with either vehicle control, 5 mg/kg prednisone, or 50 mg/kg OSU‐ERβ‐012 via daily oral gavage for four weeks. H&E staining of the mouse heart sections revealed that four of the five mice in the vehicle‐treated control group developed pericarditis, indicating that this model is both efficient and specific in recapitulating the lupus phenotype (Figure 1A and D; Supplementary Figure 2). Expectedly, the prednisone‐treated group had a reduced incidence of pericarditis with only a single positive mouse (Figure 1B and E). Interestingly, in the OSU‐ERβ‐012 treatment group, no mice exhibited evidence of pericarditis (Figure 1C and F). H&E images of all the mouse hearts are shown in Supplementary Figure 2. Pathology scoring by an experienced pathologist blinded to the treatment conditions showed a decreased trend in the scores of the mouse hearts that were treated with OSU‐ERβ‐012 (Figure 1G), which was primarily due to the severity of the pericarditis pathology seen in these mice.

Figure 1.

Figure 1

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OSU‐ERβ‐012 inhibited pericarditis induced by lupus PBMC adoptive transfer in NSG mice. Representative images of H&E stained heart sections show the gross morphology of pericarditis in the vehicle and prednisone treated mice (A & B) and the absence of pericarditis in the OSU‐ERβ‐012 treated mice (C) (magnification = 5X, scale bar = 500 μm). (D‐F) Zoomed in images of the indicated sections of A‐C (magnification = 20X, scale bar = 100 μm). Images are representative of five mice per treatment condition in the groups treated with vehicle and prednisone and four mice in the group treated with OSU‐ERβ‐012. (G) Evaluation of disease pathology did not reach statistical significance but showed a reduction in the OSU‐ERβ‐012–treated hearts.

Mouse heart sections were stained with Masson's trichrome to identify areas of fibrosis (Figure 2A–C and J), revealing significant fibrotic deposition in the inflamed pericardial tissue of the mice treated with vehicle (Figure 2A and B), whereas no such pathology existed in the mice treated with OSU‐ERβ‐012 (Figure 2J). There were also significant fibrotic lesions in the myocardium of the mice treated with vehicle (Figure 2A and C), which were nonexistent in the mice treated with OSU‐ERβ‐012, whereas two of the five mice in the group treated with prednisone manifested this pathology. Detailed images of both the pericardial and myocardial fibrosis of representative mouse hearts are shown in Figure 2, whereas Masson's trichrome images of all the mouse hearts are shown in Supplementary Figure 3.

Figure 2.

Figure 2

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Lupus‐humanized NSG mouse hearts manifested both pericarditis and myocarditis, which was inhibited by OSU‐ERβ‐012. (A) Representative image of a vehicle‐treated mouse heart section stained with Masson's trichrome demonstrating both pericardial (left box) and myocardial fibrosis (right box; magnification = 5X, scale bar = 500μm). (B, D, F, and H) Zoomed‐in images of the left box in (A), detailing the (B) pericardial fibrosis via Masson's trichrome stain and (D) the presence of macrophages, (F) T cells, and (H) neutrophils (magnification = 40X; scale bar = 50 μm). (C, E, G, and I) Zoomed‐in images of the right box in (A), detailing (C) the myocardial fibrosis via Masson's trichrome stain, (E) the presence of macrophages, and (G) the absence of T cells and (I) neutrophils (magnification = 40X; scale bar = 50 μm). (J–M) Representative images of OSU‐ERβ‐012–treated mouse heart sections. Masson's trichrome stain (J) showed the lack of fibrosis and (K) the lack of macrophages, (L) T cells, and (M) neutrophils. Quantification of cells in the hearts of treated mice shows that (N) macrophages and (O) T cells were significantly reduced in the hearts of mice treated with prednisone and with OSU‐ERβ‐012 as compared to control mice treated with vehicle (mean ± SEM). *P < 0.05. Data are representative of five mice per treatment condition in the groups treated with vehicle and prednisone and four mice in the group treated with OSU‐ERβ‐012.

IHC was performed on the mouse hearts for CD3, F4/80, CD11b, and myeloperoxidase to identify T cells, macrophages, monocytes, and neutrophils, respectively. The vehicle‐treated mouse hearts showed significant numbers of macrophages (Figure 2D) in the inflamed and fibrotic pericardium, whereas T cells and neutrophils were present but less numerous (Figure 2F and H) and monocytes were entirely absent (data not shown). Interestingly, only macrophages were present in the myocardial fibrotic lesions (Figure 2E). Quantification of these immune cell subsets revealed that the macrophages and T cells were significantly decreased in the hearts of both the mice treated with prednisone and OSU‐ERβ‐012 as compared to the mice treated with vehicle (Figure 2N and O), whereas the neutrophils showed a decreased trend in the mice treated with OSU‐ERβ‐012 but did not reach statistical significance (data not shown).

OSU‐ERβ‐012 suppresses proinflammatory cytokines

It has been well established that various cytokines play a significant role in the pathogenesis of lupus and hold promise both as potential biomarkers of clinical manifestations and as therapeutic targets. To test the hypothesis that ERβ agonism exerts a protective effect on the inflammatory cytokine profile in these mice, we assessed serum cytokine profiles at baseline and three and five weeks. The increase in circulating cytokines over this time course was evident in the mice treated with vehicle control with significantly elevated levels of interferon γ (IFNγ), interleukin‐2 (IL‐2), IL‐4, and IL‐10 (Supplementary Figure 4), demonstrating that humanization was effective at inducing a proinflammatory environment, effectively recapitulating an active lupus phenotype in these mice.

The increase in circulating IFNγ levels in the vehicle control was highly significant from baseline to three and five weeks, both of which were significantly suppressed by both OSU‐ERβ‐012 and prednisone (Supplementary Figure 4A). IL‐2 was significantly elevated over baseline at three weeks, and this elevated IL‐2 was significantly suppressed by both the OSU‐ERβ‐012 and prednisone (Supplementary Figure 4B). IL‐4 was not elevated at three weeks but was significantly elevated at five weeks, and both the OSU‐ERβ‐012 and prednisone suppressed this elevated cytokine (Supplementary Figure 4C). IL‐10 was elevated at five weeks and was also suppressed by both the OSU‐ERβ‐012 and prednisone (Supplementary Figure 4D). Tumor necrosis factor α was elevated at five weeks, but neither OSU‐ERβ‐012 nor prednisone had a significant suppressive effect (data not shown). There was no significant increase, nor were there any apparent treatment effects on IL‐1β, IL‐6, IL‐8, IL‐12p70, or IL‐13 (data not shown).

OSU‐ERβ‐012 mitigates kidney pathology

Lupus nephritis represents one of the most severe and frequent complications of SLE and a major risk factor for morbidity, potentially leading to end‐stage renal disease and death. Lupus nephritis is characterized by severe inflammatory damage leading to enlargement of the glomeruli, resulting in reduced renal filtration capacity. 26 To assess the treatment effect on kidney pathology, we measured the diameter of glomeruli in kidney sections stained with H&E. Representative glomerular images of each treatment condition are shown in Figure 3A–C. The mean glomerular size in the group treated with vehicle control was 70.6 ± 1.3 μm, which was significantly elevated as compared to the control group injected with healthy PBMCs which was 59.11 ± 1.5 μm. The group treated with prednisone was 60.5 ± 1.5 μm and the group treated with OSU‐ERβ‐012 was 57.7 ± 0.9 μm, both of which were significantly suppressed as compared to the group treated with vehicle and no different from the healthy control group (Figure 3D).

Figure 3.

Figure 3

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OSU‐ERβ‐012 mitigated glomerular inflammation. Representative glomerular images of (A) control group treated with vehicle, (B) group treated with prednisone, and (C) group treated with OSU‐ERβ‐012. (D) Quantitative results from the analysis of unbiased randomly selected glomeruli, as analyzed using the QuPath Bioimage Analysis Software, expressed as the mean glomerular diameter. The combined data from two independent experiments with a total of eight mice per treatment condition and 10 measured glomeruli from each mouse are shown (mean ± SEM). ****P < 0.0001.

DISCUSSION

OSU‐ERβ‐012 inhibited the lupus pericarditis and myocarditis phenotypes while also reducing the systemic proinflammatory cytokine response and the inflammatory renal phenotype in these NSG SLE humanized mic. Not only do our results demonstrate the potential of ERβ as a drug target for treating patients with lupus, but they also prove the specific effectiveness of this drug in treating patients with lupus with both cardiac and renal manifestations. In addition, although a model for acute pericarditis has been reported, there is no established autoimmune animal model for pericarditis. 27 Here, we have demonstrated that this lupus‐humanized NSG model is a valuable tool for translational research aimed at investigating this disease phenotype associated with lupus. The inhibition of the inflammatory profibrotic cardiac phenotype by OSU‐ERβ‐012 was particularly striking in these studies because the drug was more potent than prednisone treatment. This further demonstrates the therapeutic value of OSU‐ERβ‐012 as a very specific agonist of ERβ with less immunosuppressant potential as standard current therapies while still able to suppress clinical manifestations of the disease.

The context of cytokine production relating to the lupus phenotype and disease progression is the subject of investigation by many research groups. Much has been described about the associations of specific cytokine profiles with disease activity and/or organ pathology. In this chimeric model, we demonstrate the significant elevation of several pathogenic cytokines including IFNγ, IL‐2, IL‐4, and IL‐10. IFNγ is produced by Th1 cells and CD8+ T cells, activates macrophages, upregulates class I and class II major histocompatibility complex molecules on antigen‐presenting cells, modulates T cell differentiation, and is involved in B cell isotype switch to opsonizing and complement‐fixing antibody subclasses. 28 , 29 , 30 In the (NZB × NZW) F1 mouse model prone to lupus, disease was advanced by IFNγ administration and ameliorated by administration of an anti‐IFNγ antibody. 31 The integral role of IFNγ in lupus pathogenesis is undebatable, and the fact that OSU‐ERβ‐012 significantly inhibited IFNγ production over the five‐week experimental time course points to the promise of this drug.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Jarjour confirms that all authors have provided the final approval of the version to be published, and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements. All authors contributed to the investigation, formal analysis of the data, and writing, reviewing, and editing of the manuscript.

Supporting information

Disclosure Form:

ACR2-8-e90031-s001.pdf (483.3KB, pdf)

Supplemental Figure 1 Masson's Trichrome Images of hearts and H&E Images of hearts and kidneys from healthy human PBMC chimeric NSG mice. Five mice were humanized, numbered M1‐M5.

Supplemental Figure 2. H&E Images of hearts from lupus pericarditis humanized NSG chimeric mice.

Supplemental Figure 3. Masson's Trichrome Images of hearts and kidneys from lupus pericarditis PBMC chimeric NSG mice.

Supplemental Figure 4. Reduction of circulating inflammatory cytokines

ACR2-8-e90031-s002.pdf (2.7MB, pdf)

ACKNOWLEDGMENT

The authors would like to thank Drs Chris Coss and Chad Bennett from the Drug Development Institute for providing OSU‐ERβ‐012.

Supported by the Drug Development Institute at The Ohio State University and very kind philanthropic supporters.

Author Zeno and Dr Bruckner contributed equally to this work.

Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.90031).

Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.90031.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Disclosure Form:

ACR2-8-e90031-s001.pdf (483.3KB, pdf)

Supplemental Figure 1 Masson's Trichrome Images of hearts and H&E Images of hearts and kidneys from healthy human PBMC chimeric NSG mice. Five mice were humanized, numbered M1‐M5.

Supplemental Figure 2. H&E Images of hearts from lupus pericarditis humanized NSG chimeric mice.

Supplemental Figure 3. Masson's Trichrome Images of hearts and kidneys from lupus pericarditis PBMC chimeric NSG mice.

Supplemental Figure 4. Reduction of circulating inflammatory cytokines

ACR2-8-e90031-s002.pdf (2.7MB, pdf)

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