Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice.

Cristina González-Correa,Sofía Miñano,Miguel Romero,Rosario Jiménez,Néstor De La Visitación,Javier Moleón,Iñaki Robles-Vera,Juan Duarte,Manuel Gómez-Guzmán

doi:10.3390/antiox11010084

Abstract

Plasma levels of trimethylamine N-oxide (TMAO) are elevated in lupus patients. We analyzed the implication of TMAO in autoimmunity and vascular dysfunction of the murine model of systemic lupus erythematosus (SLE) induced by the activation of the Toll-like receptor (TLR)7 with imiquimod (IMQ). Female BALB/c mice were randomly divided into four groups: untreated control mice, control mice treated with the trimethylamine lyase inhibitor 3,3-dimethyl-1-butanol (DMB), IMQ mice, and IMQ mice treated with DMB. The DMB-treated groups were administered the substance in their drinking water for 8 weeks. Treatment with DMB reduced plasma levels of TMAO in mice with IMQ-induced lupus. DMB prevents the development of hypertension, reduces disease progression (plasma levels of anti-dsDNA autoantibodies, splenomegaly, and proteinuria), reduces polarization of T lymphocytes towards Th17/Th1 in secondary lymph organs, and improves endothelial function in mice with IMQ-induced lupus. The deleterious vascular effects caused by TMAO appear to be associated with an increase in vascular oxidative stress generated by increased NADPH oxidase activity, derived in part from the vascular infiltration of Th17/Th1 lymphocytes, and reduced nrf2-driven antioxidant defense. In conclusion, our findings identified the bacterial-derived TMAO as a regulator of immune system, allowing for the development of autoimmunity and endothelial dysfunction in SLE mice.

Highlights

Systemic lupus erythematosus (SLE) is a highly deleterious autoimmune inflammatory disease
Our group purchased seven- to nine-week-old female BALB/c mice from Janvier (Le Genest, France), which were randomly divided into 4 sized experimental groups (n = 10): an untreated control (CTR), a control group supplemented with DMB (CTR-DMB), a group treated with imiquimod (IMQ), and an IMQ-treated group supplemented with DMB (IMQ-DMB)
We could not detect any significant differences in heart rate (537.7 ± 13.4 bpm vs. 576.0 ± 27.9 bpm, CTR and IMQ groups, respectively), which was unchanged by DMB (Figure 1A)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a highly deleterious autoimmune inflammatory disease. It can be characterized by the synthesis of autoantibodies, which coalesce into immune complexes, that in turn deposit in target organs, harming the tissues. SLE has been associated with a higher risk for developing renal and cardiovascular disease [1], the most common cause of death in SLE patients [2]. Young women of child-bearing age are significantly more affected by the pathology. A link between the onset of SLE and the incidence of hypertension has been found [3]. Environmental, genetic, metabolic, and hormonal features partake in SLE predisposition [4].

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Conclusion