Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals and Experimental Groups
2.2. Blood Pressure, Morphology, and Organ Weight Indices
2.3. Plasma and Urine Parameters
2.4. Vascular Reactivity Studies
2.5. Measurement of Ex Vivo Vascular Reactive Oxygen Species (ROS) and NADPH Oxidase Activity
2.6. Flow Cytometry
2.7. Gene Expression Analysis
2.8. Statistical Analysis
3. Results
3.1. DMB Prevented High Blood Pressure, Target Organ Damage, and Proteinuria in TLR7-Dependent SLE
3.2. DMB Prevented Disease Activity Progression in TLR7-Dependent SLE
3.3. Plasma TMAO Increased in TLR7-Dependent SLE and Was Associated with Systolic Blood Pressure and Disease Activity
3.4. DMB Treatments Attenuated T-Cell Imbalance
3.5. DMB Prevented Endothelial Dysfunction, Vascular Oxidative Stress, and Th17 Vascular Infiltration
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Frostegård, J. Systemic lupus erythematosus and cardiovascular disease. Lupus 2008, 17, 364–367. [Google Scholar] [CrossRef]
- Bartels, C.M.; Buhr, K.A.; Goldberg, J.W.; Bell, C.L.; Visekruna, M.; Nekkanti, S.; Greenlee, R.T. Mortality and cardiovascular burden of systemic lupus erythematosus in a US population-based cohort. J. Rheumatol. 2014, 41, 680–687. [Google Scholar] [CrossRef]
- Al-Herz, A.; Ensworth, S.; Shojania, K.; Esdaile, J.M. Cardiovascular risk factor screening in systemic lupus erythematosus. J. Rheumatol. 2003, 30, 493–496. [Google Scholar] [PubMed]
- Wolf, V.L.; Ryan, M.J. Autoimmune Disease-Associated Hypertension. Curr. Hypertens. Rep. 2019, 21, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Taylor, E.B.; Ryan, M.J. Understanding mechanisms of hypertension in systemic lupus erythematosus. Ther. Adv. Cardiovasc. Dis. 2016, 11, 20–32. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.Q.; Szodoray, P.; Zeher, M. Toll-Like Receptor Pathways in Autoimmune Diseases. Clin. Rev. Allergy Immunol. 2016, 50, 1–17. [Google Scholar] [CrossRef] [Green Version]
- Wu, Y.W.; Tang, W.; Zuo, J.P. Toll-like receptors: Potential targets for lupus treatment. Acta Pharmacol. Sin. 2015, 36, 1395–1407. [Google Scholar] [CrossRef]
- Weidenbusch, M.; Kulkarni, O.P.; Anders, H.J. The innate immune system in human systemic lupus erythematosus. Clin. Sci. 2017, 131, 625–634. [Google Scholar] [CrossRef] [PubMed]
- Yokogawa, M.; Takaishi, M.; Nakajima, K.; Kamijima, R.; Fujimoto, C.; Kataoka, S.; Terada, Y.; Sano, S. Epicutaneous application of toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: A new model of systemic Lupus erythematosus. Arthritis Rheumatol. 2014, 66, 694–706. [Google Scholar] [CrossRef]
- Celhar, T.; Fairhurst, A.M. Modelling clinical systemic lupus erythematosus: Similarities, differences and success stories. Rheumatology 2017, 56, i88–i99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Robles-Vera, I.; Visitación, N.; Toral, M.; Sánchez, M.; Gómez-Guzmán, M.; O’valle, F.; Jiménez, R.; Duarte, J.; Romero, M. Toll-like receptor 7-driven lupus autoimmunity induces hypertension and vascular alterations in mice. J. Hypertens. 2020, 38, 1322–1335. [Google Scholar] [CrossRef] [PubMed]
- Hevia, A.; Milani, C.; López, P.; Cuervo, A.; Arboleya, S.; Duranti, S.; Turroni, F.; González, S.; Suárez, A.; Gueimonde, M.; et al. Intestinal dysbiosis associated with systemic lupus erythematosus. mBio 2014, 5, e01548-14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- López, P.; Sánchez, B.; Margolles, A.; Suárez, A. Intestinal dysbiosis in systemic lupus erythematosus: Cause or consequence? Curr. Opin. Rheumatol. 2016, 28, 515–522. [Google Scholar] [CrossRef] [PubMed]
- Luo, X.M.; Edwards, M.R.; Mu, Q.; Yu, Y.; Vieson, M.D.; Reilly, C.M.; Ahmed, S.A.; Bankole, A.A. Gut Microbiota in Human Systemic Lupus Erythematosus and a Mouse Model of Lupus. Appl. Environ. Microbiol. 2018, 84, e02288-17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, H.; Liao, X.; Sparks, J.B.; Luo, X.M. Dynamics of gut microbiota in autoimmune lupus. Appl. Environ. Microbiol. 2014, 80, 7551–7560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mu, Q.; Tavella, V.J.; Kirby, J.L.; Cecere, T.E.; Chung, M.; Lee, J.; Li, S.; Ahmed, S.A.; Eden, K.; Allen, I.C.; et al. Antibiotics ameliorate lupus-like symptoms in mice. Sci. Rep. 2017, 7, 13675. [Google Scholar] [CrossRef] [Green Version]
- Mu, Q.; Zhang, H.; Liao, X.; Lin, K.; Liu, H.; Edwards, M.R.; Ahmed, S.A.; Yuan, R.; Li, L.; Cecere, T.E.; et al. Control of lupus nephritis by changes of gut microbiota. Microbiome 2017, 5, 73. [Google Scholar] [CrossRef] [PubMed]
- Katz-Agranov, N.; Zandman-Goddard, G. The microbiome and systemic lupus erythematosus. Immunol. Res. 2017, 65, 432–437. [Google Scholar] [CrossRef]
- Manfredo Vieira, S.; Hiltensperger, M.; Kumar, V.; Zegarra-Ruiz, D.; Dehner, C.; Khan, N.; Costa, F.; Tiniakou, E.; Greiling, T.; Ruff, W.; et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 2018, 359, 1156–1161. [Google Scholar] [CrossRef] [Green Version]
- Zegarra-Ruiz, D.F.; El Beidaq, A.; Iñiguez, A.J.; Lubrano Di Ricco, M.; Manfredo Vieira, S.; Ruff, W.E.; Mubiru, D.; Fine, R.L.; Sterpka, J.; Greiling, T.M.; et al. A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity. Cell Host Microbe 2019, 25, 113–127.e6. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Zhao, F.; Wang, Y.; Chen, J.; Tao, J.; Tian, G.; Wu, S.; Liu, W.; Cui, Q.; Geng, B.; et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 2017, 5, 14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, Y.; Xu, X.; Li, M.; Cai, J.; Wei, Q.; Niu, H. Gut microbiota promote the inflammatory response in the pathogenesis of systemic lupus erythematosus. Mol. Med. 2019, 25, 35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- de la Visitación, N.; Robles-Vera, I.; Toral, M.; Gómez-Guzmán, M.; Sánchez, M.; Moleón, J.; González-Correa, C.; Martín-Morales, N.; O’Valle, F.; Jiménez, R.; et al. Gut microbiota contributes to the development of hypertension in a genetic mouse model of systemic lupus erythematosus. Br. J. Pharmacol. 2021, 178, 3708–3729. [Google Scholar] [CrossRef]
- de la Visitación, N.; Robles-Vera, I.; Moleón, J.; González-Correa, C.; Aguilera-Sánchez, N.; Toral, M.; Gómez-Guzmán, M.; Sánchez, M.; Jiménez, R.; Martin-Morales, N.; et al. Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity. Antioxidants 2021, 10, 1426. [Google Scholar] [CrossRef] [PubMed]
- de la Visitación, N.; Robles-Vera, I.; Moleón-Moya, J.; Sánchez, M.; Jiménez, R.; Gómez-Guzmán, M.; González-Correa, C.; Olivares, M.; Toral, M.; Romero, M.; et al. Probiotics prevent hypertension in a murine model of systemic lupus erythematosus induced by Toll-like receptor 7 activation. Nutrients 2021, 13, 2669. [Google Scholar] [CrossRef] [PubMed]
- Zhu, W.; Gregory, J.C.; Org, E.; Buffa, J.A.; Gupta, N.; Wang, Z.; Li, L.; Fu, X.; Wu, Y.; Mehrabian, M.; et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 2016, 165, 111–124. [Google Scholar] [CrossRef] [Green Version]
- Chen, M.L.; Zhu, X.H.; Ran, L.; Lang, H.D.; Yi, L.; Mi, M.T. Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway. J. Am. Heart Assoc. 2017, 6, e006347. [Google Scholar] [CrossRef] [PubMed]
- Brunt, V.E.; Gioscia-Ryan, R.A.; Casso, A.G.; VanDongen, N.S.; Ziemba, B.P.; Sapinsley, Z.J.; Richey, J.J.; Zigler, M.C.; Neilson, A.P.; Davy, K.P.; et al. Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans. Hypertension 2020, 76, 101–112. [Google Scholar] [CrossRef] [PubMed]
- Wu, K.; Yuan, Y.; Yu, H.; Dai, X.; Wang, S.; Sun, Z.; Wang, F.; Fei, H.; Lin, Q.; Jiang, H.; et al. The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice. Blood 2020, 136, 501–515. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.; Liang, L.; Deng, X.; Zhong, L. Lipidomic and metabolomic profiling reveals novel candidate biomarkers in active systemic lupus erythematosus. Int. J. Clin. Exp. Pathol. 2019, 12, 857–866. [Google Scholar]
- Wang, Z.; Roberts, A.B.; Buffa, J.A.; Levison, B.S.; Zhu, W.; Org, E.; Gu, X.; Huang, Y.; Zamanian-Daryoush, M.; Culley, M.K.; et al. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell 2015, 163, 1585–1595. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Marques, F.Z.; Jama, H.A.; Tsyganov, K.; Gill, P.A.; Rhys-Jones, D.; Muralitharan, R.R.; Muir, J.; Holmes, A.; Mackay, C.R. Guidelines for Transparency on Gut Microbiome Studies in Essential and Experimental Hypertension. Hypertension 2019, 74, 1279–1293. [Google Scholar] [CrossRef] [PubMed]
- Kilkenny, C.; Browne, W.; Cuthill, I.C.; Emerson, M.; Altman, D.G.; NC3Rs Reporting Guidelines Working Group. Animal research: Reporting in vivo experiments: The ARRIVE guidelines. Br. J. Pharmacol. 2010, 160, 1577–1579. [Google Scholar] [CrossRef]
- McGrath, J.C.; Lilley, E. Implementing guidelines on reporting research using animals (ARRIVE etc.): New requirements for publication in BJP. Br. J. Pharmacol. 2015, 172, 3189–3193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Souyris, M.; Mejía, J.E.; Chaumeil, J.; Guéry, J.C. Female predisposition to TLR7-driven autoimmunity: Gene dosage and the escape from X chromosome inactivation. Semin. Immunopathol. 2019, 41, 153–164. [Google Scholar] [CrossRef] [PubMed]
- Gómez-Guzmán, M.; Jiménez, R.; Romero, M.; Sánchez, M.; Zarzuelo, M.J.; Gómez-Morales, M.; O’Valle, F.; López-Farré, A.J.; Algieri, F.; Gálvez, J.; et al. Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. Hypertension 2014, 64, 330–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Toral, M.; Robles-Vera, I.; Romero, M.; de la Visitación, N.; Sánchez, M.; O’Valle, F.; Rodriguez-Nogales, A.; Gálvez, J.; Duarte, J.; Jiménez, R. Lactobacillus fermentum CECT5716: A novel alternative for the prevention of vascular disorders in a mouse model of systemic lupus erythematosus. FASEB J. 2019, 33, 10005–10018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Z.; Levison, B.S.; Hazen, J.E.; Donahue, L.; Li, X.M.; Hazen, S.L. Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal. Biochem. 2014, 455, 35–40. [Google Scholar] [CrossRef] [Green Version]
- Toral, M.; Romero, M.; Rodríguez-Nogales, A.; Jiménez, R.; Robles-Vera, I.; Algieri, F.; Chueca-Porcuna, N.; Sánchez, M.; de la Visitación, N.; Olivares, M.; et al. Lactobacillus fermentum Improves Tacrolimus-Induced Hypertension by Restoring Vascular Redox State and Improving eNOS Coupling. Mol. Nutr. Food Res. 2018, 62, e1800033. [Google Scholar] [CrossRef]
- Romero, M.; Toral, M.; Robles-Vera, I.; Sánchez, M.; Jiménez, R.; O’Valle, F.; Rodriguez-Nogales, A.; Pérez-Vizcaino, F.; Gálvez, J.; Duarte, J. Activation of Peroxisome Proliferator Activator Receptor β/δ Improves Endothelial Dysfunction and Protects Kidney in Murine Lupus. Hypertension 2017, 69, 641–650. [Google Scholar] [CrossRef] [PubMed]
- Talaat, R.M.; Mohamed, S.F.; Bassyouni, I.H.; Raouf, A.A. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine 2015, 72, 146–153. [Google Scholar] [CrossRef]
- Xing, C.; Sestak, A.L.; Kelly, J.A.; Nguyen, K.L.; Bruner, G.R.; Harley, J.B.; Gray-McGuire, C. Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: Interaction with 2p11, 12q24 and 19q13 in European Americans. Hum. Genet. 2007, 120, 623–631. [Google Scholar] [CrossRef]
- Jiang, T.; Tian, F.; Zheng, H.; Whitman, S.A.; Lin, Y.; Zhang, Z.; Zhang, N.; Zhang, D.D. Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response. Kidney Int. 2014, 85, 333–343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, X.; Li, Y.; Yang, P.; Liu, X.; Lu, L.; Chen, Y.; Zhong, X.; Li, Z.; Liu, H.; Ou, C.; et al. Trimethylamine-N-Oxide Promotes Vascular Calcification Through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-κB (Nuclear Factor κB) Signals. Arterioscler. Thromb. Vasc. Biol. 2020, 40, 751–765. [Google Scholar] [CrossRef] [PubMed]
- Higashi, M.; Shimokawa, H.; Hattori, T.; Hiroki, J.; Mukai, Y.; Morikawa, K.; Ichiki, T.; Takahashi, S.; Takeshita, A. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: Effect on endothelial NAD(P)H oxidase system. Circ. Res. 2003, 93, 767–775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guan, P.; Liang, Y.; Wang, N. Fasudil alleviates pressure overload-induced heart failure by activating Nrf2-mediated antioxidant responses. J. Cell Biochem. 2018, 119, 6452–6460. [Google Scholar] [CrossRef]
- Robles-Vera, I.; Toral, M.; Duarte, J. Microbiota and Hypertension: Role of the Sympathetic Nervous System and the Immune System. Am. J. Hypertens. 2020, 33, 890–901. [Google Scholar] [CrossRef]
- Dar, O.; Salaman, M.R.; Seifert, M.H.; Isenberg, D.A. B lymphocyte activation in systemic lupus erythematosus: Spontaneous production of IgG antibodies to DNA and environmental antigens in cultures of blood mononuclear cells. Clin. Exp. Immunol. 1988, 73, 430–435. [Google Scholar] [PubMed]
- Ye, Y.; Liu, M.; Tang, L.; Du, F.; Liu, Y.; Hao, P.; Fu, Q.; Guo, Q.; Yan, Q.; Zhang, X.; et al. Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis. Arthritis Res. Ther. 2019, 21, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, G.; Pan, B.; Chen, Y.; Guo, C.; Zhao, M.; Zheng, L.; Chen, B. Trimethylamine N-oxide in atherogenesis: Impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci. Rep. 2017, 37, BSR20160244. [Google Scholar] [CrossRef] [Green Version]
- Zhang, M.; Yu, G.; Chan, B.; Pearson, J.T.; Rathanaswami, P.; Delaney, J.; Ching Lim, A.; Babcook, J.; Hsu, H.; Gavin, M.A. Interleukin-21 receptor blockade inhibits secondary humoral responses and halts the progression of preestablished disease in the (NZB × NZW) F1 systemic lupus erythematosus model. Arthritis Rheumatol. 2015, 67, 2723–2731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mathis, K.W.; Wallace, K.; Flynn, E.R.; Maric-Bilkan, C.; LaMarca, B.; Ryan, M.J. Preventing autoimmunity protects against the development of hypertension and renal injury. Hypertension 2014, 64, 792–800. [Google Scholar] [CrossRef] [Green Version]
- Alunno, A.; Bartoloni, E.; Bistoni, O.; Nocentini, G.; Ronchetti, S.; Caterbi, S.; Valentini, V.; Riccardi, C.; Gerli, R. Balance between regulatory T and Th17 cells in systemic lupus erythematosus: The old and the new. Clin. Dev. Immunol. 2012, 2012, 823085. [Google Scholar] [CrossRef]
- Liu, Y.; Seto, N.L.; Carmona-Rivera, C.; Kaplan, M.J. Accelerated model of lupus autoimmunity and vasculopathy driven by toll-like receptor 7/9 imbalance. Lupus Sci. Med. 2018, 5, e000259. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, H.; Chiasson, V.L.; Chatterjee, P.; Kopriva, S.E.; Young, K.J.; Mitchell, B.M. Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc. Res. 2013, 97, 696–704. [Google Scholar] [CrossRef] [Green Version]
- Pietrowski, E.; Bender, B.; Huppert, J.; White, R.; Luhmann, H.J.; Kuhlmann, C.R. Pro-inflammatory effects of interleukin-17A on vascular smooth muscle cells involve NAD(P)H-oxidase derived reactive oxygen species. J. Vasc. Res. 2011, 48, 52–58. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
González-Correa, C.; Moleón, J.; Miñano, S.; Visitación, N.d.l.; Robles-Vera, I.; Gómez-Guzmán, M.; Jiménez, R.; Romero, M.; Duarte, J. 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
González-Correa C, Moleón J, Miñano S, Visitación Ndl, Robles-Vera I, Gómez-Guzmán M, Jiménez R, Romero M, Duarte J. Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice. Antioxidants. 2022; 11(1):84. https://doi.org/10.3390/antiox11010084
Chicago/Turabian StyleGonzález-Correa, Cristina, Javier Moleón, Sofía Miñano, Néstor de la Visitación, Iñaki Robles-Vera, Manuel Gómez-Guzmán, Rosario Jiménez, Miguel Romero, and Juan Duarte. 2022. "Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice" Antioxidants 11, no. 1: 84. https://doi.org/10.3390/antiox11010084
APA StyleGonzález-Correa, C., Moleón, J., Miñano, S., Visitación, N. d. l., Robles-Vera, I., Gómez-Guzmán, M., Jiménez, R., Romero, M., & Duarte, J. (2022). Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice. Antioxidants, 11(1), 84. https://doi.org/10.3390/antiox11010084