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

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Date

2021-12-29

Authors

Gonzalez-Correa, Cristina
Moleon, Javier
Miñano, Sofia
Visitacion, Nestor de la
Robles-Vera, Iñaki
Gomez-Guzman, Manuel
Jimenez, Rosario
Romero, Miguel
Duarte, Juan

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MDPI AG
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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.

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MeSH Terms

trimethyloxamine
Antioxidants
1-Butanol
trimethylamine
Drinking Water
Imiquimod
Mice, Inbred BALB C
NF-E2-Related Factor 2
Autoimmunity
T-Lymphocytes
Butanols
Toll-Like Receptor 7
Disease Models, Animal
anti-dsDNA autoantibody
Splenomegaly
Oxidative Stress
Proteinuria

DeCS Terms

1-Butanol
Agua potable
Antioxidantes
Autoanticuerpos
Autoinmunidad
Butanoles
Esplenomegalia
Estrés oxidativo
Factor 2 relacionado con NF-E2 imiquimod
Linfocitos T
Modelos animales de enfermedad proteinuria
Ratones endogámicos BALB C
Receptor Toll-Like 7

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Keywords

3,3-dimethyl-1-butanol, cardiovascular complications, hypertension, systemic lupus erythematosus, trimethylamine N-oxide

Citation

González-Correa C, Moleón J, Miñano S, Visitación N, Robles-Vera I, Gómez-Guzmán M, et al. Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice. Antioxidants (Basel). 2021 Dec 30;11(1):84.