Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors
Corresponding Author
Sandra Sacre
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Dr. Sacre has filed a patent application for the use of selective serotonin reuptake inhibitors in the treatment of arthritis (no financial benefit to declare).
Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9RY, UKSearch for more papers by this authorMino Medghalchi
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Search for more papers by this authorBernard Gregory
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Search for more papers by this authorFionula Brennan
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Dr. Brennan has received consulting fees, speaking fees, and/or honoraria from Wyeth (less than $10,000).
Search for more papers by this authorRichard Williams
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Search for more papers by this authorCorresponding Author
Sandra Sacre
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Dr. Sacre has filed a patent application for the use of selective serotonin reuptake inhibitors in the treatment of arthritis (no financial benefit to declare).
Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9RY, UKSearch for more papers by this authorMino Medghalchi
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Search for more papers by this authorBernard Gregory
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Search for more papers by this authorFionula Brennan
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Dr. Brennan has received consulting fees, speaking fees, and/or honoraria from Wyeth (less than $10,000).
Search for more papers by this authorRichard Williams
Kennedy Institute of Rheumatology, Imperial College of Science, Technology, and Medicine, London, UK
Search for more papers by this authorAbstract
Objective
Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA).
Methods
Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs.
Results
Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-γ–inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action.
Conclusion
Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development.
REFERENCES
- 1 Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397–440.
- 2 Drexler S, Sacre SM, Foxwell BM. Toll-like receptors: a new target in rheumatoid arthritis? Expert Rev Clin Immunol 2006; 2: 585–99.
- 3 Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009; 21: 317–37.
- 4 Wagner H. Endogenous TLR ligands and autoimmunity. Adv Immunol 2006; 91: 159–73.
- 5 Uematsu S, Akira S. Toll-like receptors and innate immunity. J Mol Med 2006; 84: 712–25.
- 6 Popa C, Abdollahi-Roodsaz S, Joosten LA, Takahashi N, Sprong T, Matera G, et al. Bartonella quintana lipopolysaccharide is a natural antagonist of Toll-like receptor 4. Infect Immun 2007; 75: 4831–7.
- 7 Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, Radstake TR, Matera G, Popa C, et al. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 2007; 56: 2957–67.
- 8 Choe JY, Crain B, Wu SR, Corr M. Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor 4 signaling. J Exp Med 2003; 197: 537–42.
- 9 Iwahashi M, Yamamura M, Aita T, Okamoto A, Ueno A, Ogawa N, et al. Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum 2004; 50: 1457–67.
- 10 Sacre SM, Lo A, Gregory B, Simmonds RE, Williams L, Feldmann M, et al. Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures. J Immunol 2008; 181: 8002–9.
- 11 Sacre SM, Andreakos E, Kiriakidis S, Amjadi P, Lundberg A, Giddins G, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol 2007; 170: 518–25.
- 12 Radstake TR, Roelofs MF, Jenniskens YM, Oppers-Walgreen B, van Riel PL, Barrera P, et al. Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-γ. Arthritis Rheum 2004; 50: 3856–65.
- 13 Seibl R, Birchler T, Loeliger S, Hossle JP, Gay RE, Saurenmann T, et al. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 2003; 162: 1221–7.
- 14 Foell D, Wittkowski H, Roth J. Mechanisms of disease: a ‘DAMP’ view of inflammatory arthritis. Nat Clin Pract Rheumatol 2007; 3: 382–90.
- 15 Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 2009; 15: 774–80.
- 16 Maes M. The immunoregulatory effects of antidepressants. Hum Psychopharmacol 2001; 16: 95–103.
- 17 Smith RS. The macrophage theory of depression. Med Hypotheses 1991; 35: 298–306.
- 18 Tsao CW, Lin YS, Chen CC, Bai CH, Wu SR. Cytokines and serotonin transporter in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 899–905.
- 19 Basterzi AD, Aydemir C, Kisa C, Aksaray S, Tuzer V, Yazici K, et al. IL-6 levels decrease with SSRI treatment in patients with major depression. Hum Psychopharmacol 2005; 20: 473–6.
- 20 O'Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 2007; 41: 326–31.
- 21 Levin J, Bang FB. The role of endotoxin in the extracellular coagulation of Limulus blood. Bull Johns Hopkins Hosp 1964; 115: 265–74.
- 22 Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989; 2: 244–7.
- 23 Brennan FM, Chantry D, Jackson AM, Maini RN, Feldmann M. Cytokine production in culture by cells isolated from the synovial membrane. J Autoimmun 1989; 2 Suppl: 177–86.
- 24 Butler DM, Feldmann M, Di Padova F, Brennan FM. p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. Eur Cytokine Netw 1994; 5: 441–8.
- 25 Foxwell B, Browne K, Bondeson J, Clarke C, de Martin R, Brennan F, et al. Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor α production in rheumatoid arthritis is NF-κB dependent. Proc Natl Acad Sci U S A 1998; 95: 8211–5.
- 26 Buchan G, Barrett K, Turner M, Chantry D, Maini RN, Feldmann M. Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1α. Clin Exp Immunol 1988; 73: 449–55.
- 27 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.
- 28 Holmdahl R, Bockermann R, Backlund J, Yamada H. The molecular pathogenesis of collagen-induced arthritis in mice: a model for rheumatoid arthritis. Ageing Res Rev 2002; 1: 135–47.
- 29 Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303: 1526–9.
- 30 Lundberg A, Drexler SK, Monaco C, Williams LM, Sacre SM, Feldmann M, et al. Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. Blood 2007; 110: 3245–52.
- 31 Kyburz D, Rethage J, Seibl R, Lauener R, Gay RE, Carson DA, et al. Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by Toll-like receptor signaling. Arthritis Rheum 2003; 48: 642–50.
- 32 Poeck H, Wagner M, Battiany J, Rothenfusser S, Wellisch D, Hornung V, et al. Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 2004; 103: 3058–64.
- 33 Mossner R, Lesch KP. Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav Immun 1998; 12: 249–71.
- 34 Van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet 1993; 24: 203–20.
- 35 Diamond M, Kelly JP, Connor TJ. Antidepressants suppress production of the Th1 cytokine interferon-γ, independent of monoamine transporter blockade. Eur Neuropsychopharmacol 2006; 16: 481–90.
- 36 Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. Anti-inflammatory effects of antidepressants through suppression of the interferon-γ/interleukin-10 production ratio. J Clin Psychopharmacol 2001; 21: 199–206.
- 37 O'Neill LA. Primer: Toll-like receptor signaling pathways: What do rheumatologists need to know? Nat Clin Pract Rheumatol 2008; 4: 319–27.
- 38 Roelofs MF, Wenink MH, Brentano F, Abdollahi-Roodsaz S, Oppers-Walgreen B, Barrera P, et al. Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis 2009; 68: 1486–93.
- 39 Brentano F, Schorr O, Gay RE, Gay S, Kyburz D. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum 2005; 52: 2656–65.
- 40 Kim KW, Cho ML, Oh HJ, Kim HR, Kang CM, Heo YM, et al. TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. Immunol Lett 2009; 124: 9–17.
- 41 Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001; 194: 863–9.
- 42 Hayashi T, Gray CS, Chan M, Tawatao RI, Ronacher L, McGargill MA, et al. Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7. Proc Natl Acad Sci U S A 2009; 106: 2764–9.
- 43 Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity 2003; 19: 837–47.
- 44 Suarez-Almazor ME, Belseck E, Shea B, Homik J, Wells G, Tugwell P. Antimalarials for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000; 4:CD000959.
- 45 Kyburz D, Brentano F, Gay S. Mode of action of hydroxychloroquine in RA: evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Pract Rheumatol 2006; 2: 458–9.
- 46 Isnardi I, Ng YS, Srdanovic I, Motaghedi R, Rudchenko S, von Bernuth H, et al. IRAK-4-and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. Immunity 2008; 29: 746–57.
- 47 Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 2006; 7: 156–64.
- 48 Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A, Yang K, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 2006; 314: 308–12.
- 49 Sancho-Shimizu V, Zhang SY, Abel L, Tardieu M, Rozenberg F, Jouanguy E, et al. Genetic susceptibility to herpes simplex virus 1 encephalitis in mice and humans. Curr Opin Allergy Clin Immunol 2007; 7: 495–505.
- 50 Samuels J, Ng YS, Coupillaud C, Paget D, Meffre E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med 2005; 201: 1659–67.
- 51 Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997; 340: 249–58.
- 52 Reis M, Aamo T, Spigset O, Ahlner J. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit 2009; 31: 42–56.
- 53 Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 2008; 452: 234–8.
