Lupus pathogenesis and autoimmunity are exacerbated by high fat diet–induced obesity in MRL/lpr mice

Abstract

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by persistent inflammation and autoantibody production, leading to systemic damage. Genetic predisposition and environmental factors such as high fat diet (HFD)/obesity may contribute to lupus development. In this study, we investigated the impact of HFD in lupus pathogenesis and autoimmunity to reveal the pathological link of HFD and SLE using-lupus prone mice.Methods: Sixty MRL/lpr mice were grouped and fed with a regular diet (RD) or HFD. Their body weights were recorded weekly. SLE progression was monitored by skin lesion, urine protein, and titers of anti-dsDNA and antinuclear antibodies (ANA). Mice were euthanized at week 14. Kidney and skin tissue sections were stained with hematoxylin and eosin (H&E), periodic acid–Schiff (PAS), and Masson's trichrome to detect lupus histopathological lesions and were quantified as kidney index and histological skin score. Immune cells in the spleen were identified by immunofluorescence staining and flow cytometry. Student t test or two-way ANOVA was used for statistical analysis.Results: HFD induced a significant increase in mouse body weight by week 5 and continued until week 14 compared to RD (p<0.05 to p<0.01). Skin lesions resembling human discoid lupus were observed as early as week 6 and became severe at week 14 in 55.6% of the HFD group compared to 11.1% of the RD group (p<0.05). Proteinuria occurred from week 11 to week 14 in the HFD group. Splenomegaly was observed in the HFD mice (p<0.05). The HFD group had a higher histological skin score and kidney index than the RD group. An increased trend of anti-dsDNA antibody was detected in the HFD group but no difference in ANA was seen between HFD and RD groups. A significant increase of germinal center B cells and plasma cells was observed in the spleens of HFD mice. The percentage of Tfh cells and the ratio of Tfh/Treg were significantly increased in the HFD group (p<0.05). Conclusion: Our results showed that HFD induced an accelerated and exacerbated lupus development and autoimmunity in MRL/lpr mice. Tfh/Treg cells may be the interconnection of HFD and SLE. Interventions of healthy diet or restoring balance of Tfh/Treg cells may improve both lupus symptoms and outcomes in genetically predisposed SLE patients.