Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Development of Relapsing–Remitting (RR) Experimental Autoimmune Encephalomyelitis (EAE) in SJL/J Mice
2.3. Experimental Groups
2.4. Real-Time PCR
2.5. Protein Expression Analsyis by Flow Cytometry in Splenocytes
2.6. Evaluation of TrxR Activity in the CNS
2.7. Evaluation of Nrf2 Binding Activity in the CNS by ELISA
2.8. Evaluation of p-NFkB, Lipid Peroxides, and Myeloperoxidase Activity in the CNS
2.9. Statistical Analysis
3. Results
3.1. AFN Leads to the Amelioration of the Clinical Symptoms in SJL/J Mice with the RR Type of EAE
3.2. AFN Causes the Inhibition of TrxR Activity and the Upregulation of Nrf2 in the CNS of Immunized SJL/J Mice
3.3. AFN Causes the Inhibition of NFkB Signaling in the CNS of Immunized SJL/J Mice
3.4. AFN Causes the Upregulation of Nrf2 Signaling in Peripheral Myeloid Immune Cells in Immunized SJL/J Mice
3.5. AFN Causes the Downregulation of Oxidative Stress and Inflammatory Mediators in Peripheral Myeloid Cells in Immunized SJL/J Mice
3.6. AFN Causes the Upregulation of Nrf2 Signaling in Peripheral Lymphoid Immune Cells (CD3+ T Cells) in Immunized SJL/J Mice
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Dendrou, C.A.; Fugger, L.; Friese, M.A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 2015, 15, 545–558. [Google Scholar] [CrossRef] [PubMed]
- Bebo, B.; Cintina, I.; Larocca, N.; Ritter, L.; Talente, B.; Hartung, D.; Ngorsuraches, S.; Wallin, M.; Yang, G. The economic burden of multiple sclerosis in the United States: Estimate of direct and indirect costs. Neurology 2022, 98, e1810–e1817. [Google Scholar] [CrossRef] [PubMed]
- Cree, B.A.C.; Arnold, D.L.; Chataway, J.; Chitnis, T.; Fox, R.J.; Pozo Ramajo, A.; Murphy, N.; Lassmann, H. Secondary progressive multiple sclerosis: New insights. Neurology 2021, 97, 378–388. [Google Scholar] [CrossRef] [PubMed]
- Hollen, C.; Neilson, L.E.; Barajas, R.F., Jr.; Greenhouse, I.; Spain, R.I. Oxidative stress in multiple sclerosis-Emerging imaging techniques. Front. Neurol. 2023, 13, 1025659. [Google Scholar] [CrossRef] [PubMed]
- Larochelle, C.; Alvarez, J.I.; Prat, A. How do immune cells overcome the blood-brain barrier in multiple sclerosis? FEBS Lett. 2011, 585, 3770–3780. [Google Scholar] [CrossRef]
- Compston, A.; Coles, A. Multiple sclerosis. Lancet 2008, 372, 1502–1517. [Google Scholar] [CrossRef] [PubMed]
- Ratzer, R.; Søndergaard, H.B.; Christensen, J.R.; Börnsen, L.; Borup, R.; Sørensen, P.S.; Sellebjerg, F. Gene expression analysis of relapsing-remitting, primary progressive and secondary progressive multiple sclerosis. Mult. Scler. 2013, 19, 1841–1848. [Google Scholar] [CrossRef]
- Achiron, A.; Gurevich, M.; Friedman, N.; Kaminski, N.; Mandel, M. Blood transcriptional signatures of multiple sclerosis: Unique gene expression of disease activity. Ann. Neurol. 2004, 55, 410–417. [Google Scholar] [CrossRef]
- Ajami, B.; Samusik, N.; Wieghofer, P.; Ho, P.P.; Crotti, A.; Bjornson, Z.; Prinz, M.; Fantl, W.J.; Nolan, G.P.; Steinman, L. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 2018, 21, 541–551. [Google Scholar] [CrossRef]
- Costa, S.; Bevilacqua, D.; Cassatella, M.A.; Scapini, P. Recent advances on the crosstalk between neutrophils and B or T lymphocytes. Immunology 2019, 156, 23–32. [Google Scholar] [CrossRef]
- Prame Kumar, K.; Nicholls, A.J.; Wong, C.H.Y. Partners in crime: Neutrophils and monocytes/macrophages in inflammation and disease. Cell Tissue Res. 2018, 371, 551–565. [Google Scholar] [CrossRef] [PubMed]
- Madeira, J.M.; Renschler, C.J.; Mueller, B.; Hashioka, S.; Gibson, D.L.; Klegeris, A. Novel protective properties of auranofin: Inhibition of human astrocyte cytotoxic secretions and direct neuroprotection. Life Sci. 2013, 92, 1072–1080. [Google Scholar] [CrossRef] [PubMed]
- Sonzogni-Desautels, K.; Ndao, M. Will Auranofin Become a Golden New Treatment Against COVID-19? Front. Immunol. 2021, 12, 683694. [Google Scholar] [CrossRef] [PubMed]
- Upīte, J.; Kadish, I.; van Groen, T.; Jansone, B. Subchronic administration of auranofin reduced amyloid-β plaque pathology in a transgenic APPNL-G-F/NL-G-F mouse model. Brain Res. 2020, 1746, 147022. [Google Scholar] [CrossRef]
- Hwangbo, H.; Kim, M.Y.; Ji, S.Y.; Kim, S.Y.; Lee, H.; Kim, G.Y.; Park, C.; Keum, Y.S.; Hong, S.H.; Cheong, J.; et al. Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro. Antioxidants 2020, 9, 1040. [Google Scholar] [CrossRef] [PubMed]
- Tindell, R.; Wall, S.B.; Li, Q.; Li, R.; Dunigan, K.; Wood, R.; Tipple, T.E. Selenium supplementation of lung epithelial cells enhances nuclear factor E2-related factor 2 (Nrf2) activation following thioredoxin reductase inhibition. Redox Biol. 2018, 19, 331–338. [Google Scholar] [CrossRef]
- Lee, S.M.; Koh, D.H.; Jun, D.W.; Roh, Y.J.; Kang, H.T.; Oh, J.H.; Kim, H.S. Auranofin attenuates hepatic steatosis and fibrosis in nonalcoholic fatty liver disease via NRF2 and NF- κB signaling pathways. Clin. Mol. Hepatol. 2022, 28, 827–840. [Google Scholar] [CrossRef]
- Dedoni, S.; Scherma, M.; Camoglio, C.; Siddi, C.; Dazzi, L.; Puliga, R.; Frau, J.; Cocco, E.; Fadda, P. An overall view of the most common experimental models for multiple sclerosis. Neurobiol. Dis. 2023, 184, 106230. [Google Scholar] [CrossRef]
- Zhan, J.; Mann, T.; Joost, S.; Behrangi, N.; Frank, M.; Kipp, M. The Cuprizone Model: Dos and Do Nots. Cells 2020, 9, 843. [Google Scholar] [CrossRef]
- Cebula, M.; Schmidt, E.E.; Arnér, E.S. TrxR1 as a potent regulator of the Nrf2-Keap1 response system. Antioxid. Redox Signal. 2015, 23, 823–853. [Google Scholar] [CrossRef]
- Locy, M.L.; Rogers, L.K.; Prigge, J.R.; Schmidt, E.E.; Arnér, E.S.; Tipple, T.E. Thioredoxin reductase inhibition elicits Nrf2-mediated responses in Clara cells: Implications for oxidant-induced lung injury. Antioxid. Redox Signal. 2012, 17, 1407–1416. [Google Scholar] [CrossRef] [PubMed]
- Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25, 402–408. [Google Scholar] [CrossRef] [PubMed]
- Nadeem, A.; Ahmad, S.F.; Al-Harbi, N.O.; Sarawi, W.; Attia, S.M.; Alanazi, W.A.; Ibrahim, K.E.; Alsanea, S.; Alqarni, S.A.; Alfardan, A.S.; et al. Acetyl-11-keto-β-boswellic acid improves clinical symptoms through modulation of Nrf2 and NF-κB pathways in SJL/J mouse model of experimental autoimmune encephalomyelitis. Int. Immunopharmacol. 2022, 107, 108703. [Google Scholar] [CrossRef]
- Al-Harbi, N.O.; Nadeem, A.; Ahmad, S.F.; Bakheet, S.A.; El-Sherbeeny, A.M.; Ibrahim, K.E.; Alzahrani, K.S.; Al-Harbi, M.M.; Mahmood, H.M.; Alqahtani, F.; et al. Therapeutic treatment with Ibrutinib attenuates imiquimod-induced psoriasis-like inflammation in mice through downregulation of oxidative and inflammatory mediators in neutrophils and dendritic cells. Eur. J. Pharmacol. 2020, 877, 173088. [Google Scholar] [CrossRef] [PubMed]
- Hey, Y.Y.; Tan, J.K.; O’Neill, H.C. Redefining Myeloid Cell Subsets in Murine Spleen. Front. Immunol. 2016, 6, 652. [Google Scholar] [CrossRef] [PubMed]
- Nadeem, A.; Ahmad, S.F.; Al-Harbi, N.O.; El-Sherbeeny, A.M.; Alasmari, A.F.; Alanazi, W.A.; Alasmari, F.; Ibrahim, K.E.; Al-Harbi, M.M.; Bakheet, S.A. Bruton’s tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells. Int. Immunopharmacol. 2020, 80, 106215. [Google Scholar] [CrossRef] [PubMed]
- Bjørklund, G.; Zou, L.; Peana, M.; Chasapis, C.T.; Hangan, T.; Lu, J.; Maes, M. The Role of the Thioredoxin System in Brain Diseases. Antioxidants 2022, 11, 2161. [Google Scholar] [CrossRef]
- Solleiro-Villavicencio, H.; Rivas-Arancibia, S. Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases. Front. Cell Neurosci. 2018, 12, 114. [Google Scholar] [CrossRef]
- Pennisi, G.; Cornelius, C.; Cavallaro, M.M.; Salinaro, A.T.; Cambria, M.T.; Pennisi, M.; Bella, R.; Milone, P.; Ventimiglia, B.; Migliore, M.R.; et al. Redox regulation of cellular stress response in multiple sclerosis. Biochem. Pharmacol. 2011, 82, 1490–1499. [Google Scholar] [CrossRef]
- Yevgi, R.; Demir, R. Oxidative stress activity of fingolimod in multiple sclerosis. Clin. Neurol. Neurosurg. 2021, 202, 106500. [Google Scholar] [CrossRef]
- Bibi, T.; Khan, A.; Khan, A.U.; Shal, B.; Ali, H.; Seo, E.K.; Khan, S. Magnolol prevented brain injury through the modulation of Nrf2-dependent oxidative stress and apoptosis in PLP-induced mouse model of multiple sclerosis. Naunyn Schmiedebergs Arch Pharmacol. 2022, 395, 717–733. [Google Scholar] [CrossRef] [PubMed]
- De Bondt, M.; Hellings, N.; Opdenakker, G.; Struyf, S. Neutrophils: Underestimated Players in the Pathogenesis of Multiple Sclerosis (MS). Int. J. Mol. Sci. 2020, 21, 4558. [Google Scholar] [CrossRef] [PubMed]
- Naegele, M.; Tillack, K.; Reinhardt, S.; Schippling, S.; Martin, R.; Sospedra, M. Neutrophils in multiple sclerosis are characterized by a primed phenotype. J. Neuroimmunol. 2012, 242, 60–71. [Google Scholar] [CrossRef] [PubMed]
- Lévesque, S.A.; Paré, A.; Mailhot, B.; Bellver-Landete, V.; Kébir, H.; Lécuyer, M.A.; Alvarez, J.I.; Prat, A.; de Rivero Vaccari, J.P.; Keane, R.W.; et al. Myeloid cell transmigration across the CNS vasculature triggers IL-1β-driven neuroinflammation during autoimmune encephalomyelitis in mice. J. Exp. Med. 2016, 213, 929–949. [Google Scholar] [CrossRef] [PubMed]
- Greter, M.; Heppner, F.L.; Lemos, M.P.; Odermatt, B.M.; Goebels, N.; Laufer, T.; Noelle, R.J.; Becher, B. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 2005, 11, 328–334. [Google Scholar] [CrossRef]
- Michaličková, D.; Hrnčíř, T.; Canová, N.K.; Slanař, O. Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis. Eur. J. Pharmacol. 2020, 873, 172973. [Google Scholar] [CrossRef] [PubMed]
- Maldonado, P.P.; Guevara, C.; Olesen, M.A.; Orellana, J.A.; Quintanilla, R.A.; Ortiz, F.C. Neurodegeneration in Multiple Sclerosis: The Role of Nrf2-Dependent Pathways. Antioxidants 2022, 11, 1146. [Google Scholar] [CrossRef]
- Yu, Z.; Fang, X.; Liu, W.; Sun, R.; Zhou, J.; Pu, Y.; Zhao, M.; Sun, D.; Xiang, Z.; Liu, P.; et al. Microglia Regulate Blood-Brain Barrier Integrity via MiR-126a-5p/MMP9 Axis during Inflammatory Demyelination. Adv. Sci. 2022, 9, e2105442. [Google Scholar] [CrossRef]
- Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 2009, 9, 393–407. [Google Scholar] [CrossRef]
- Lu, H.C.; Kim, S.; Steelman, A.J.; Tracy, K.; Zhou, B.; Michaud, D.; Hillhouse, A.E.; Konganti, K.; Li, J. STAT3 signaling in myeloid cells promotes pathogenic myelin-specific T cell differentiation and autoimmune demyelination. Proc. Natl. Acad. Sci. USA 2020, 117, 5430–5441. [Google Scholar] [CrossRef]
- Segal, B.M. Th17 cells in autoimmune demyelinating disease. Semin. Immunopathol. 2010, 32, 71–77. [Google Scholar] [CrossRef] [PubMed]
- Sonar, S.A.; Lal, G. Differentiation and Transmigration of CD4 T Cells in Neuroinflammation and Autoimmunity. Front. Immunol. 2017, 8, 1695. [Google Scholar] [CrossRef] [PubMed]
- McGinley, A.M.; Sutton, C.E.; Edwards, S.C.; Leane, C.M.; DeCourcey, J.; Teijeiro, A.; Hamilton, J.A.; Boon, L.; Djouder, N.; Mills, K.H. Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1β-Producing Myeloid Cells that Promote Pathogenic T Cells. Immunity 2020, 52, 342–356. [Google Scholar] [CrossRef] [PubMed]
- Alhazzani, K.; Ahmad, S.F.; Al-Harbi, N.O.; Attia, S.M.; Bakheet, S.A.; Sarawi, W.; Alqarni, S.A.; Algahtani, M.; Nadeem, A. Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing-Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice. Pharmaceutics 2021, 13, 925. [Google Scholar] [CrossRef] [PubMed]
- Algahtani, M.M.; Alshehri, S.; Alqarni, S.S.; Ahmad, S.F.; Al-Harbi, N.O.; Alqarni, S.A.; Alfardan, A.S.; Ibrahim, K.E.; Attia, S.M.; Nadeem, A. Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice. Int. J. Mol. Sci. 2023, 24, 8101. [Google Scholar] [CrossRef] [PubMed]
- Mantovani, A.; Cassatella, M.A.; Costantini, C.; Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 2011, 11, 519–531. [Google Scholar] [CrossRef] [PubMed]
- Steinbach, K.; Piedavent, M.; Bauer, S.; Neumann, J.T.; Friese, M.A. Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. J. Immunol. 2013, 191, 4531–4539. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Ray, A.; Miller, N.M.; Hartwig, D.; Pritchard, K.A.; Dittel, B.N. Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood-brain barrier integrity and ameliorates disease severity. J. Neurochem. 2016, 136, 826–836. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Wu, H.; Gao, C.; Yang, D.; Yang, D.; Shen, J. Radix Rehmanniae Extract Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing Macrophage-Derived Nitrative Damage. Front. Physiol. 2018, 9, 864. [Google Scholar] [CrossRef] [PubMed]
- Saha, S.; Buttari, B.; Panieri, E.; Profumo, E.; Saso, L. An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules 2020, 25, 5474. [Google Scholar] [CrossRef]
- Zakrzewska-Pniewska, B.; Styczynska, M.; Podlecka, A.; Samocka, R.; Peplonska, B.; Barcikowska, M.; Kwiecinski, H. Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis. Mult. Scler. 2004, 10, 266–271. [Google Scholar] [CrossRef]
- Cong, H.; Zhang, M.; Chang, H.; Du, L.; Zhang, X.; Yin, L. Icariin ameliorates the progression of experimental autoimmune encephalomyelitis by down-regulating the major inflammatory signal pathways in a mouse relapse-remission model of multiple sclerosis. Eur. J. Pharmacol. 2020, 885, 173523. [Google Scholar] [CrossRef]
- Lassmann, H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front. Immunol. 2019, 9, 3116. [Google Scholar] [CrossRef]
- Bhargava, P.; Kim, S.; Reyes, A.A.; Grenningloh, R.; Boschert, U.; Absinta, M.; Pardo, C.; Van Zijl, P.; Zhang, J.; Calabresi, P.A. Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition. Brain 2021, 144, 1396–1408. [Google Scholar] [CrossRef]
- Preziosa, P.; Pagani, E.; Bonacchi, R.; Cacciaguerra, L.; Falini, A.; Rocca, M.A.; Filippi, M. In vivo detection of damage in multiple sclerosis cortex and cortical lesions using NODDI. J. Neurol. Neurosurg. Psychiatry 2022, 93, 628–636. [Google Scholar] [CrossRef] [PubMed]
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Al-Kharashi, L.A.; Al-Harbi, N.O.; Ahmad, S.F.; Attia, S.M.; Algahtani, M.M.; Ibrahim, K.E.; Bakheet, S.A.; Alanazi, M.M.; Alqarni, S.A.; Alsanea, S.; et al. Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE. Biomedicines 2023, 11, 2502. https://doi.org/10.3390/biomedicines11092502
Al-Kharashi LA, Al-Harbi NO, Ahmad SF, Attia SM, Algahtani MM, Ibrahim KE, Bakheet SA, Alanazi MM, Alqarni SA, Alsanea S, et al. Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE. Biomedicines. 2023; 11(9):2502. https://doi.org/10.3390/biomedicines11092502
Chicago/Turabian StyleAl-Kharashi, Layla A., Naif O. Al-Harbi, Sheikh F. Ahmad, Sabry M. Attia, Mohammad M. Algahtani, Khalid E. Ibrahim, Saleh A. Bakheet, Mohammed M. Alanazi, Saleh A. Alqarni, Sary Alsanea, and et al. 2023. "Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE" Biomedicines 11, no. 9: 2502. https://doi.org/10.3390/biomedicines11092502