Vol 9, No 1 (2023)
Research paper
Published online: 2023-03-21

open access

Page views 482
Article views/downloads 331
Get Citation

Connect on Social Media

Connect on Social Media

Tryptophan metabolism via the kynurenine pathway in selected rheumatic diseases: A review of the literature

Joanna Witoszyńska-Sobkowiak1, Dorota Sikorska1, Włodzimierz Samborski1
Rheumatology Forum 2023;9(1):3-10.

Abstract

In chronic inflammatory diseases, as a result of pro-inflammatory cytokines, the enzyme indoleamine 2,3-dioxygenase (IDO) is excessively activated, resulting in increased tryptophan metabolism via the kynurenine pathway (KP). Both IDO and metabolites of the KP affect cells of the immune system, mainly T lymphocytes. In this way, they exert an immunosuppressive effect, reducing inflammation. Also in rheumatic diseases such as rheumatoid arthritis (RA), osteoporosis, osteoarthritis and ankylosing spondylitis, there is excessive activation of the KP. This publication reports on disorders of tryptophan metabolism found in the above-mentioned disease entities.

Article available in PDF format

View PDF Download PDF file

References

  1. Tanaka M, Bohár Z, Vécsei L. Are kynurenines accomplices or principal villains in dementia? Maintenance of kynurenine metabolism. Molecules. 2020; 25(3): 564.
  2. Castro-Portuguez R, Sutphin GL. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: targeting tryptophan metabolism to promote longevity and healthspan. Exp Gerontol. 2020; 132: 110841.
  3. Marx W, McGuinness AJ, Rocks T, et al. The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies. Mol Psychiatry. 2021; 26(8): 4158–4178.
  4. Wirthgen E, Hoeflich A, Rebl A, et al. Kynurenic acid: the Janus-faced role of an immunomodulatory tryptophan metabolite and its link to pathological conditions. Front Immunol. 2017; 8: 1957.
  5. Tanaka M, Tóth F, Polyák H, et al. Immune influencers in action: metabolites and enzymes of the tryptophan-kynurenine metabolic pathway. Biomedicines. 2021; 9(7): 734.
  6. Mancuso R, Hernis A, Agostini S, et al. Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS One. 2015; 10(6): e0130715.
  7. Filippini P, Del Papa N, Sambataro D, et al. Emerging concepts on inhibitors of indoleamine 2,3-dioxygenase in rheumatic diseases. Curr Med Chem. 2012; 19(31): 5381–5393.
  8. Nikolaus S, Schulte B, Al-Massad N, et al. Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases. Gastroenterology. 2017; 153(6): 1504–1516.e2.
  9. Eryavuz Onmaz D, Sivrikaya A, Isik K, et al. Altered kynurenine pathway metabolism in patients with ankylosing spondylitis. Int Immunopharmacol. 2021; 99: 108018.
  10. Åkesson K, Pettersson S, Ståhl S, et al. Kynurenine pathway is altered in patients with SLE and associated with severe fatigue. Lupus Sci Med. 2018; 5(1): e000254.
  11. de Oliveira FR, Fantucci MZ, Adriano L, et al. Neurological and inflammatory manifestations in Sjögren's syndrome: the role of the kynurenine metabolic pathway. Int J Mol Sci. 2018; 19(12): 3953.
  12. Harden JL, Egilmez NK. Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity. Immunol Invest. 2012; 41(6-7): 738–764.
  13. Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998; 281(5380): 1191–1193.
  14. Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: is it an immune suppressor? Cancer J. 2010; 16(4): 354–359.
  15. Ravishankar B, Liu H, Shinde R, et al. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2012; 109(10): 3909–3914.
  16. Ogbechi J, Clanchy FI, Huang YS, et al. IDO activation, inflammation and musculoskeletal disease. Exp Gerontol. 2020; 131: 110820.
  17. Williams RO. Exploitation of the IDO pathway in the therapy of rheumatoid arthritis. Int J Tryptophan Res. 2013; 6(Suppl 1): 67–73.
  18. Kim SY, Oh Y, Jo S, et al. Inhibition of human osteoclast differentiation by kynurenine through the aryl-hydrocarbon receptor pathway. Cells. 2021; 10(12): 3498.
  19. Panfili E, Gerli R, Grohmann U, et al. Amino acid metabolism in rheumatoid arthritis: friend or foe? Biomolecules. 2020; 10(9): 1280.
  20. Lin YJ, Anzaghe M, Schülke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells. 2020; 9(4): 880.
  21. Schroecksnadel K, Kaser S, Ledochowski M, et al. Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J Rheumatol. 2003; 30(9): 1935–1939.
  22. Igari T, Tsuchizawa M, Shimamura T. Alteration of tryptophan metabolism in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. Tohoku J Exp Med. 1987; 153(2): 79–86.
  23. Schroecksnadel K, Winkler C, Duftner C, et al. Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin Rheumatol. 2006; 25(3): 334–337.
  24. Szanto S, Koreny T, Mikecz K, et al. Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice. Arthritis Res Ther. 2007; 9(3): R50.
  25. Criado G, Simelyte E, Inglis JJ, et al. Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum. 2009; 60(5): 1342–1351.
  26. Merlo LMF, Pigott E, DuHadaway JB, et al. IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J Immunol. 2014; 192(5): 2082–2090.
  27. Prendergast GC, Chang MY, Mandik-Nayak L, et al. Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr Med Chem. 2011; 18(15): 2257–2262.
  28. Scott GN, DuHadaway J, Pigott E, et al. The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J Immunol. 2009; 182(12): 7509–7517.
  29. Tykocinski LO, Lauffer AM, Bohnen A, et al. Synovial fibroblasts selectively suppress Th1 cell responses through IDO1-mediated tryptophan catabolism. J Immunol. 2017; 198(8): 3109–3117.
  30. Parada-Turska J, Zgrajka W, Majdan M. Kynurenic acid in synovial fluid and serum of patients with rheumatoid arthritis, spondyloarthropathy, and osteoarthritis. J Rheumatol. 2013; 40(6): 903–909.
  31. Parada-Turska J, Rzeski W, Zgrajka W, et al. Kynurenic acid, an endogenous constituent of rheumatoid arthritis synovial fluid, inhibits proliferation of synoviocytes in vitro. Rheumatol Int. 2006; 26(5): 422–426.
  32. Huang YS, Ogbechi J, Clanchy FI, et al. IDO and kynurenine metabolites in peripheral and CNS disorders. Front Immunol. 2020; 11: 388.
  33. Prendergast GC, Metz R, Muller AJ, et al. IDO2 in immunomodulation and autoimmune disease. Front Immunol. 2014; 5: 585.
  34. Alahdal M, Duan L, Ouyang H, et al. The role of indoleamine 2,3-dioxygenase 1 in the osteoarthritis. Am J Transl Res. 2020 ; 12(6): 2322–2343.
  35. Brown JP. Long-term treatment of postmenopausal osteoporosis. Endocrinol Metab (Seoul). 2021; 36(3): 544–552.
  36. Forrest CM, Mackay GM, Oxford L, et al. Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment. Clin Exp Pharmacol Physiol. 2006; 33(11): 1078–1087.
  37. Eisa NH, Reddy SV, Elmansi AM, et al. Kynurenine promotes RANKL-induced osteoclastogenesis in vitro by activating the aryl hydrocarbon receptor pathway. Int J Mol Sci. 2020; 21(21): 7931.
  38. Lorenzo J. The many ways of osteoclast activation. J Clin Invest. 2017; 127(7): 2530–2532.
  39. Wada T, Nakashima T, Hiroshi N, et al. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006; 12(1): 17–25.
  40. Michalowska M, Znorko B, Kaminski T, et al. New insights into tryptophan and its metabolites in the regulation of bone metabolism. J Physiol Pharmacol. 2015; 66(6): 779–791.
  41. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017; 390(10089): 73–84.
  42. Huang T, Pu Y, Wang X, et al. Metabolomic analysis in spondyloarthritis: A systematic review. Front Microbiol. 2022; 13: 965709.
  43. Al Saedi A, Sharma S, Summers MA, et al. The multiple faces of tryptophan in bone biology. Exp Gerontol. 2020; 129: 110778.
  44. Klavdianou K, Liossis SN, Papachristou DJ, et al. Decreased serotonin levels and serotonin-mediated osteoblastic inhibitory signaling in patients with ankylosing spondylitis. J Bone Miner Res. 2016; 31(3): 630–639.
  45. Sornasse T, Li L, Zhao S, et al. Putative role of the histidine and tryptophan biochemical pathways in the mode of action of upadacitinib in patients with ankylosing spondylitis [abstract]. Arthritis Rheumatol. 2022; 74 (Suppl 9). https://acrabstracts.org/abstract/putative-role-of-the-histidine-and-tryptophan-biochemical-pathways-in-the-mode-of-action-of-upadacitinib-in-patients-with-ankylosing-spondylitis/ (3.11.2022).
  46. Hornyák L, Dobos N, Koncz G, et al. The role of indoleamine-2,3-dioxygenase in cancer development, diagnostics, and therapy. Front Immunol. 2018; 9: 151.