Establishment of a novel lupus mesenteric vasculitis mouse model and exploration of its exacerbation mechanisms

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.