Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice González Correa, Cristina Moleón Moya, Javier Miñano, Sofía de la Visitación, Néstor Robles Vera, Iñaki Gómez Guzmán, Manuel Jiménez Moleón, Rosario Romero Pérez, Miguel Duarte Pérez, Juan Manuel Systemic lupus erythematosus Trimethylamine N-oxide 3,3-dimethyl-1-butanol Hypertension Cardiovascular complications This work was supported by Grants from Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad (MINECO) (SAF2017-84894-R), Ministerio de Ciencia e Innovacion (MCIN)/Agencia Estatal de Investigacion (AEI)/10.13039/501100011033 (PID2020-116347RB-I00), Junta de Andalucia (CTS 164, P20_00193) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV). J.M. and C.G.C. are predoctoral fellows of MINECO and Junta de Andalucia, respectively. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, FEDER una manera de hacer Europa). 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 bacterialderived TMAO as a regulator of immune system, allowing for the development of autoimmunity and endothelial dysfunction in SLE mice. 2022-03-07T12:17:16Z 2022-03-07T12:17:16Z 2021-12-30 journal article González-Correa, C... [et al.]. Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice. Antioxidants 2022, 11, 84. [https://doi.org/10.3390/antiox11010084] http://hdl.handle.net/10481/73190 10.3390/antiox11010084 eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España MDPI