---
title: "Lupus Mesenteric Vasculitis Mouse Model: Article Content Not Provided by Source"
id: "frontiers-in-immunology-14-establishment-of-a-novel-lupus-mesenteric-vasculitis-mouse-model-and"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-14-establishment-of-a-novel-lupus-mesenteric-vasculitis-mouse-model-and"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1886325"
published_at: "2026-09-09T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Lupus Mesenteric Vasculitis Mouse Model: Article Content Not Provided by Source
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1886325)
- **Published At:** 2026-09-09T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source article text was not included in the provided SOURCE JINA body; the webpage content available was navigation and site structure rather than the research report itself. No experimental details, results, figures, or conclusions from the study were present in the supplied text. - Because the full article content was not provided, specific information about the establishment of a **lupus mesenteric vasculitis** **mouse model**, experimental protocols, or outcomes could not be extracted or summarized from the source. - The supplied material did not report the methods used to induce disease, animal strains, sample sizes, control groups, or ethical approvals; these critical methodological details were absent. - No results were available in the provided source text: there were no reported histology, imaging, immunologic assays, molecular findings, or quantitative endpoints describing the model or mechanisms of exacerbation. - The source did not include any mechanistic data, such as signaling pathways, immune cell involvement, cytokine profiles, genetic manipulations, or pharmacologic interventions relevant to disease exacerbation. - No discussion, interpretation, clinical relevance, limitations, or future directions from the authors were present in the provided content. - Any reader seeking valid clinical or experimental takeaways must consult the full article at the publisher site, because the supplied SOURCE JINA body lacks substantive article content and thus contains no extractable study facts or conclusions.
## Clinical Analysis & Structured Key Points
Frontiers | Establishment of a novel lupus mesenteric vasculitis mouse model and exploration of its exacerbation mechanisms ORIGINAL RESEARCH article Front. Immunol. , 09 September 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1886325 Published in Frontiers in Immunology Autoimmune Disorders 7 impact factor 11.3 citescore Editor & Reviewers Edited by R W Ryu Watanabe Reviewed by Y M Yuichi Maeda Q P Qingjun Pan Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Figure 7 View in article Table 1 Continuous stimulation with R848 induced fecal occult blood positivity in NZBWF1 (BWF1) mice. View in article Table 2 Frequency of fecal occult blood positivity in LMV-induced mice with and without antibiotic treatment. View in article ORIGINAL RESEARCH article Front. Immunol. , 09 September 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1886325 Establishment of a novel lupus mesenteric vasculitis mouse model and exploration of its exacerbation mechanisms M F Maki Fujishiro 1 K H Kunihiro Hayakawa 1 * Y K Yuko Kataoka 1 M S Marina Shinoura 1 H T Hiroyuki Tomita 1 Y S Yuna Saito 1 T N Takuya Nishi 2 K I Keigo Ikeda 2 K T Kenji Takamori 1 I S Iwao Sekigawa 1,2 † +2 more S M Shinji Morimoto 2 1. Institute for Environment and Gender-Specific Medicine, Graduate School of Medicine, Juntendo University, Chiba, Japan 2. Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, Chiba, Japan Article metrics View details Abstract Lupus mesenteric vasculitis (LMV) is a gastrointestinal lesion primarily caused by vasculitis associated with systemic lupus erythematosus (SLE). In our preliminary experiments, we found that NZBWF1 (BWF1) mice, a spontaneous SLE mouse model, developed bloody stools when treated with imiquimod, a Toll-like receptor (TLR) 7 agonist. Therefore, in this study, we investigated the effects of the continuous application of a TLR7/8 agonist resiquimod (R848) on the gastrointestinal tract in BWF1 mice. To address this, 8-week-old female BWF1 mice were treated with R848 three times weekly for up to 6 weeks. We found that R848-treated mice developed intestinal vasculitis. In addition, these mice exhibited significantly increased serum autoantibody levels and accelerated SLE pathology. Because these symptoms closely resemble human LMV pathology, we established this as a novel inducible LMV mouse model. To elucidate the mechanisms underlying the onset and exacerbation of LMV, we analyzed changes in the intestinal environment. LMV-induced mice showed altered intestinal microbiota and increased fecal levels of propionic acid, an intestinal microbiota metabolite. To investigate the effect of bacteria on LMV pathogenesis, we treated LMV-induced mice with broad-spectrum antibiotics and found that this treatment tended to suppress LMV pathology early in the induction period. Furthermore, propionate administration appeared to attenuate intestinal vasculitis in these mice. Thus, we found that increased intestinal propionate contributes to attenuating LMV pathology. In conclusion, we established an inducible LMV mouse model by R848 treatment of BWF1 mice. Using this induced LMV mouse model, the pathophysiology of LMV can be analyzed in detail. Additionally, our findings suggest that bacteria influence the induction and exacerbation of LMV pathogenesis, and that intestinal propionate may be involved in maintaining homeostasis. In the future, this LMV mouse model may contribute to the development of new diagnostic and therapeutic methods. 1 Introduction Lupus mesenteric vasculitis (LMV) is a gastrointestinal lesion that is associated with systemic lupus erythematosus (SLE). LMV is rare complication of SLE and frequently presents with acute abdominal pain ( 1 – 3 ). The symptoms of LMV, such as abdominal pain, nausea, vomiting, ascites and diarrhea, are similar to those of infections enteritis, and there are no distinctive clinical findings ( 4 ). Therefore, early diagnosis and treatment are difficult, especially when it presents as an initial manifestation of SLE ( 2 ). Diagnosis primarily involves blood tests, imaging, and pathology ( 4 ). Pathologically, vasculitis is observed in the subserosa of the small intestine ( 5 ). However, because pathological evaluation is highly invasive and difficult to perform, the diagnosis is mainly based on a comprehensive assessment of imaging findings, such as intestinal wall thickening, intestinal wall enhancement (target sign), and engorgement of mesenteric vessels (comb sign) ( 2 ). Furthermore, while LMV is effectively treated with steroids and immunosuppressants ( 1 ), there are concerns about the side effects of their long-term use ( 6 ). Therefore, clarifying the mechanisms of LMV onset and exacerbation could lead to the development of LMV-specific diagnostic and therapeutic methods in the future. However, currently, the mechanisms underlying LMV onset and exacerbation remain elusive, as no mouse models that exhibit its pathology have been established. SLE is a prototypical autoimmune disease characterized by multi-organ damage caused by the production of diverse autoantibodies, deposition of immune complexes in tissues, and infiltration of inflammatory cells ( 7 ). SLE is triggered not only by genetic factors but also by environmental factors such as ultraviolet radiation, viral infections, and female hormones. Regarding environmental triggers, antiviral defense mechanisms are closely associated with Toll-like receptors (TLRs). Specifically, TLR7 functions as a sensor for single-stranded RNA (ssRNA) viruses, such as influenza virus and coronavirus, as well as self-derived ssRNA ( 8 ). In addition, aberrant TLR7 signaling plays a crucial role in the pathogenesis of SLE in both humans and mice ( 9 – 11 ). Consistent with these findings, topical application of a TLR7 agonist induces SLE-like autoimmune pathology in wild-type mice ( 11 ). Based on these findings, we previously demonstrated that continuous treatment of NZBWF1 (BWF1) mice, a spontaneous SLE model, with the TLR7 agonist imiquimod (IMQ) led to the early onset of lupus nephritis ( 12 ). Interestingly, during these experiments, we discovered that the IMQ-treated mice developed markedly bloody stools. Therefore, in this study, based on our observation in IMQ-treated mice, we investigated the underlying mechanisms of bloody stools using an R848-induced mouse model. Specifically, we aimed to elucidate whether excessive TLR7/8 signaling induced by continuous application of the TLR7/8 agonist R848 causes intestinal lesions, and whether this gastrointestinal phenotype reflects the pathogenesis of LMV. 2 Materials and methods 2.1 Mice and in vivo treatment All mouse experiments were approved by and performed in accordance with the Institutional Animal Care and Use Committee of Juntendo University (approval numbers: 310237, 2020094, 2021091, 2022070, 2023082, 2024110, 2025048) and conducted in accordance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. Female NZBWF1 (BWF1), male BXSB, and female MRL/MpJ- Fas lpr (MRL/ lpr ) mice were purchased from Japan SLC (Hamamatsu, Japan). Female BALB/c mice were purchased from Jackson Laboratory Japan (Yokohama, Japan). BXSB mice and MRL/ lpr mice were utilized as SLE model mice in addition to the BWF1 strain, with BALB/c mice serving as wild-type controls. To normalize the intestinal flora, mice were housed in our animal facility for at least 4 weeks prior to the start of the experiments. All mice were randomly assigned to groups and housed at 3–6 mice per cage. BWF1 mice used in this study were selected based on the absence of increased serum anti-dsDNA antibody titers at 8 weeks of age. The number of mice in all experiments is provided in the figure legends. To induce autoimmunity via TLR7 overactivation, resiquimod (R848), a synthetic TLR7/8 agonist, was primarily utilized. BWF1 mice were treated with 10 µg of R848 (Enzo Life Sciences, Farmingdale, NY) three times per week via topical application to the skin on one side of the pinna for up to 6 weeks. Similarly, R848 was administered to other strains starting at the following ages: 1) BXSB mice from 6 weeks of age, 2) MRL/ lpr mice from 5 weeks of age, and 3) BALB/c mice from 8 weeks of age. The treatment duration was 3 weeks for BXSB and MRL/ lpr mice, and 6 weeks for BALB/c mice. In addition, IMQ cream (Beselna Cream; Mochida Pharmaceutical, Tokyo, Japan), a selective TLR7 agonist, was utilized as an alternative to R848. IMQ cream (1.25 µL) was applied to the skin on one side of the pinna three times per week used for 6 weeks. To investigate the role of the intestinal microbiota, antibiotics were administered to deplete intestinal bacteria. The antibiotic mixture consisted of vancomycin (0.5 g/L; FUJIFILM Wako, Osaka, Japan), neomycin (1.0 g/L; FUJIFILM Wako), ampicillin (1.0 g/L; Nacalai Tesque, Kyoto, Japan), and metronidazole (0.5 g/L or 1.0 g/L; FUJIFILM Wako) in drinking water ( 13 ). The administration of antibiotics was initiated 3 weeks before R848 application. Metronidazole was administered at a concentration of 0.5 g/L during the first week as an acclimatization period, and the concentration was subsequently increased to 1.0 g/L from the second week onwards. Sodium propionate (150 mM; Sigma-Aldrich Japan, Tokyo, Japan) was dissolved in the drinking water and provided ad libitum ( 14 ). The sodium propionate solution was administered concurrently with the R848 application for 3 weeks. 2.2 Clinical examination Serum anti-dsDNA antibody levels (specific for IgG) were measured using a mouse anti-dsDNA antibody ELISA kit (FUJIFILM Wako Shibayagi, Shibukawa, Japan). Total IgG levels were determined using an ELISA kit (Thermo Fisher Scientific, Waltham, MA). Fecal occult blood was measured by the o -tolidine colorimetric method. Platelet counts were determined using whole blood anticoagulated with EDTA-2Na. Urinalysis was performed to qualitatively assess proteinuria. Proteinuria was measured using urine test strips (Uropaper III, EIKEN, Tokyo, Japan) and scored as − ( 2000 mg/dL), according to the manufacturer’s scoring system. Anti-neutrophil cytoplasmic antibodies (ANCA) were evaluated as follows: bone marrow was collected from BALB/c mouse, and neutrophils were isolated using an EasySep mouse neutrophil enrichment kit (STEMCELL Tec, Vancouver, Canada). The isolated neutrophils were attached to slides. The prepared slides were incubated with 10-fold diluted serum from BWF1 mice treated with or without R848 for 30 min at 37°C. Subsequently, bound antibodies were detected using Alexa Fluor 488-conjugated donkey anti-mouse IgG (1:200; Invitrogen, Carlsbad, CA) and observed under a fluorescence microscope (BZ-X800; Keyence, Osaka, Japan). 2.3 Flow cytometry Platelet-associated IgG (PAIgG) was measured using whole blood anticoagulated with ACD-A solution (2.2 w/v% sodium citrate hydrate, 0.8 w/v% citric acid hydrate, and 2.2 w/v% glucose). Samples for staining were prepared by removing erythrocytes from whole blood using Lysing Buffer (BD Biosciences, San Jose, CA). These samples were stained with predetermined optimal concentrations of antibodies ( Supplementary Table 1 ) for 20 min at 4°C, washed in FACS buffer (PBS containing 0.1% BSA and 0.09% sodium azide), and then stained with optimal concentrations of appropriate fluorochrome-conjugated streptavidin for 20 min at 4°C. Cells were analyzed using FACSCalibur and LSRFortessa X-20 flow cytometers (BD Biosciences), and data were analyzed using FlowJo software (V10.8.1, BD Biosciences). 2.4 Histopathological analysis Murine ileum, kidney, and liver tissues were fixed in 20% formalin and embedded in paraffin. The tissues were sectioned and stained as follows: the ileum (3-µm thickness) with hematoxylin-eosin (HE), Elastica van Gieson (EVG), and Victoria blue-HE (VB-HE); the liver (3-µm thickness) with HE and Elastica Masson stain; and the kidney (2-µm thickness) with HE and periodic acid-Schiff (PAS). The Swiss roll technique for intestinal pathology was performed based on a previously described ( 15 ). Histological staining reagents were obtained from MUTO PURE CHEMICALS (Tokyo, Japan). Renal tissue injury was evaluated using the modified National Institutes of Health lupus nephritis activity and chronicity indices ( 16 ). All histological evaluations were performed by three independent investigators, at least two of whom were blinded to group allocation. For immunofluorescence staining, the ileum and kidneys were embedded in OCT Compound (Sakura Finetek Japan, Tokyo, Japan), snap-frozen, sectioned at a 3 µm or 10 µm thickness and fixed in 4% paraformaldehyde. The ileum sections were immunostained with the antibodies listed in Supplementary Table 1 . Histopathological specimens were observed using fluorescence and optical microscopy (BZ-X800; Keyence). Locally infiltrating cells were counted in up to three high-power fields (×200 magnification) per section by three investigators, and the mean number of cells per field was calculated for each animal. When evaluable fields were limited due to insufficient pathological section quality, the analysis was performed using the average of the available fields of view. 2.5 Intestinal flora and fecal metabolite analyses Fecal samples from mice in each group were pooled prior to extraction. Total DNA was extracted from these pooled samples using a NucleoSpin DNA stool kit (TaKaRa, Kusatsu, Japan) according to the manufacturer’s instructions. Intestinal microbiota metagenomic analysis was performed by the Primary Cell Division of Cosmo Bio., Ltd. (Sapporo, Japan) using 16S rRNA gene amplicon sequencing on an Illumina MiSeq platform. The obtained raw paired-end reads data were merged using FLASH (Fast Length Adjustment of Short reads) software to combine paired-end reads. The assembled sequences were then subjected to noise reduction using CD-HIT-OTU/rDNATools, and bacterial species comprising the clustered OTUs (Operational Taxonomic Units) were identified and compared. Fecal metabolite analysis was performed by TechnoSuruga Laboratory Co., Ltd. (Shizuoka, Japan) using gas chromatography with a flame ionization detector (GC-FID, 7890B, Agilent Technologies, Santa Clara, CA, USA) or high-performance liquid chromatography (HPLC, Organic acid analysis system, Shimadzu, Kyoto, Japan). The following compounds were measured: 1) short-chain fatty acids (acetic acid, propionic acid, n-butyric acid, isobutyric acid, n-valeric acid, isovaleric acid, and n-caproic acid) and 2) organic acids (succinic acid, lactic acid, and formic acid). For GC-FID measurement, 100 mg of each fecal sample was placed in a bead tube, and mixed with nine-fold volume of 0.5% phosphoric acid solution, and heat treatment at 85°C for 15 min. Next, the samples were homogenized with beads and centrifuged. An equal volume of ethyl acetate was added to the supernatant and mixed. Subsequently, an internal standard was added to the ethyl acetate layer recovered by centrifugation, and the target metabolites were quantified using GC-FID. For HPLC measurements, fecal samples were placed in bead tubes, extraction reagents were added, and heat-treated at 85°C for 15 min. The homogenized samples were centrifuged, and the supernatants were filtered through a 0.2 µm membrane filter. The filtrates were then quantitatively analyzed by HPLC using 5 mmol/L p-toluenesulfonic acid as the eluent, and 5 mmol/L p-toluenesulfonic acid, 100 µmol/L EDTA, and 20 mmol/L Bis-Tris as the reaction mixture. Because the measurement methods differed, the data were normalized prior to comparison. Fecal samples for these analyses were collected after 3 weeks of R848 treatment. The results were compared between the R848 (−) and R848 (+) groups. 2.6 Cells Human umbilical vein endothelial cells (HUVEC) were obtained from Lonza (Basel, Switzerland), and human aortic smooth muscle cells (HAoSMC) were obtained from PromoCell (Heidelberg, Germany). HUVEC were maintained in EGM™-2 BulletKit (Lonza), and HAoSMC were maintained in Smooth Muscle Cell Basal Medium 2 (PromoCell). 2.7 In vitro cell assays HUVEC were stimulated for 6 hours or 24 hours with IL-1β (10 ng/mL; R&D Systems, Minneapolis, MN, USA), TNF-α (10 ng/mL; R&D Systems), lipopolysaccharide (LPS; 0.5 µg/mL; Escherichia coli O111:B4; Sigma-Aldrich Japan), sodium propionate (1.5 mM; Sigma-Aldrich Japan), or trichostatin A (TSA; 1 nM; FUJIFILM Wako) alone, or in combination with an inflammatory stimulus (IL-1β, TNF-α, or LPS) and either sodium propionate or TSA. The cells were then subjected to quantitative polymerase chain reaction (qPCR) or western blotting. The assay medium was EBM-2 (Lonza) supplemented with 0.2% fetal bovine serum (FBS). HAoSMC were treated with or without sodium propionate (1.5 mM) or sodium butyrate (1.5 mM; FUJIFILM Wako) for 48 hours or 7 days, and were then subjected to western blotting. The assay medium was RPMI-1640 (Sigma-Aldrich Japan, Tokyo, Japan) supplemented with 1% FBS. 2.8 RNA extraction and quantitative polymerase chain reaction Total RNA was extracted from mouse ileum, kidney, and human cell lines, and reverse transcription-qPCR was performed as previously described ( 12 ). Briefly, total RNA was extracted using ISOGEN II (Nippon Gene, Tokyo, Japan) or an RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturers instructions. The extracted RNA was reverse transcribed with PrimeScript RT Reagent Kit (TaKaRa). qPCR was performed using TB Green Premix Ex Taq (TaKaRa) on a QuantStudio 5 or QuantStudio 6 (Thermo Fisher Scientific). The data were quantified using standard curves and evaluated relative to the expression levels of Gapdh or Actb (mouse) and ACTB (human). In some experiments, the data were normalized to Gapdh (mouse) and calculated using the comparative Ct (ΔΔCt) method. Specific primer sequences are listed in Supplementary Table 2 . 2.9 Western blotting HUVEC and HAoSMC were lysed with RIPA buffer (BioDynamics Laboratory Inc., Tokyo, Japan), and SDS-PAGE and western blotting were performed as previously described ( 17 ). The antibodies used for western blotting were listed in Supplementary Table 1 . Densitometric analysis was performed using ImageJ software (Rasband, W.S., ImageJ, U.S. National Institutes of Health, Bethesda, MD, USA). 2.10 Statistical analysis Statistical analyses were performed using GraphPad Prism 10 software (GraphPad Software, La Jolla, CA, USA). In the animal study, differences between groups were compared using Student’s t -test (parametric test for two groups), Mann-Whitney U test (nonparametric test for two groups), a one-way ANOVA followed by Sidak’s multiple-comparison test (for multiple groups), and Fisher’s exact test (for fecal occult blood testing). In the cell culture studies, differences between groups were compared using a one-way ANOVA followed by Sidak’s multiple-comparison test (for multiple groups). 3 Results 3.1 Continuous administration of R848 to young female mice induced intestinal lesions We continuously administered R848 to BWF1 mice and observed the resulting phenotype. Repeated treatment with R848 significantly induced bloody stools in the treatment group from 3 to 6 weeks post-treatment. Fecal occult blood tests became positive at 3 weeks after R848 treatment ( Table 1 ). At 6 weeks post-treatment, macroscopic bleeding was observed in the small intestine ( Supplementary Figure 1A ). Based on these symptoms, we considered the possibility of LMV. Because lesions in LMV often appear from the jejunum to the ileum ( 4 ), we prepared and observed Swiss roll preparations of the small intestine. HE staini
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