Vol 10, No 1 (2024)
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Published online: 2024-01-24

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Influence of inflammation on tryptophan metabolism in chronic rheumatic diseases: the role of the kynurenine pathway in an interferon-dependent mechanism in systemic lupus erythematosus and primary Sjögren's syndrome — a literature review

Joanna Witoszyńska-Sobkowiak1, Dorota Sikorska1, Włodzimierz Samborski1
Rheumatology Forum 2024;10(1):17-25.


Under physiological conditions, the metabolism of tryptophan (TRP), an endogenous amino acid, leads to the formation of the neurotransmitters regulating mood and sleep and wakefulness patterns — serotonin and melatonin, among others. In inflammation, it is metabolised predominantly along the kynurenine pathway. This is caused by activation by pro-inflammatory cytokines [e.g. interferon (IFN) or tumour necrosis factor alpha (TNF-α)] of one of the enzymes: indoleamine 2,3-dioxygenase (IDO), which catabolises the synthesis of kynurenine (KYN) from TRP. Products of the kynurenine pathway, such as KYN, kynurenic acid, 3-hydroxykynurenine and quinolinic acid, are neuroactive and immunomodulatory substances. Elevated IFN levels and increased IDO activity are characteristic of chronic autoimmune diseases, including systemic lupus erythematosus and Sjögren's syndrome. This article reports on the role of the kynurenine pathway in the above diseases.

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  1. Del Papa N, Minniti A, Lorini M, et al. The Role of Interferons in the Pathogenesis of Sjögren's Syndrome and Future Therapeutic Perspectives. Biomolecules. 2021; 11(2).
  2. Rönnblom L, Leonard D. Interferon pathway in SLE: one key to unlocking the mystery of the disease. Lupus Sci Med. 2019; 6(1): e000270.
  3. Postal M, Vivaldo JF, Fernandez-Ruiz R, et al. Type I interferon in the pathogenesis of systemic lupus erythematosus. Curr Opin Immunol. 2020; 67: 87–94.
  4. 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.
  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).
  6. Buczko P, Cylwik D, Stokowska W. Metabolizm tryptofanu w ślinie szlakiem kinureninowym. Postępy Hig Med Dosw. 2005; 59: 283–289.
  7. Dantzer R, O'Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008; 9(1): 46–56.
  8. Tanaka M, Bohár Z, Vécsei L. Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism. Molecules. 2020; 25(3).
  9. Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020; 25(1): 131–147.
  10. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957; 147(927): 258–267.
  11. Chasset F, Dayer JM, Chizzolini C. Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment. Front Pharmacol. 2021; 12: 633821.
  12. Thorlacius GE, Wahren-Herlenius M, Rönnblom L. An update on the role of type I interferons in systemic lupus erythematosus and Sjögren's syndrome. Curr Opin Rheumatol. 2018; 30(5): 471–481.
  13. 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.
  14. Harden JL, Egilmez NK. Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity. Immunol Invest. 2012; 41(6-7): 738–764.
  15. Huang YS, Ogbechi J, Clanchy FI, et al. IDO and Kynurenine Metabolites in Peripheral and CNS Disorders. Front Immunol. 2020; 11: 388.
  16. Karageorgas T, Fragioudaki S, Nezos A, et al. Fatigue in Primary Sjögren's Syndrome: Clinical, Laboratory, Psychometric, and Biologic Associations. Arthritis Care Res (Hoboken). 2016; 68(1): 123–131.
  17. Fanouriakis A, Tziolos N, Bertsias G, et al. Update οn the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021; 80(1): 14–25.
  18. Shaikh MF, Jordan N, D'Cruz DP. Systemic lupus erythematosus. Clin Med (Lond). 2017; 17(1): 78–83.
  19. Majdan M. Toczeń rumieniowaty układowy. In: Terapia w chorobach reumatycznych. PZWL, Warszawa 2018: 129–151.
  20. Oke V, Gunnarsson I, Dorschner J, et al. High levels of circulating interferons type I, type II and type III associate with distinct clinical features of active systemic lupus erythematosus. Arthritis Res Ther. 2019; 21(1): 107.
  21. Bengtsson AA, Trygg J, Wuttge DM, et al. Metabolic Profiling of Systemic Lupus Erythematosus and Comparison with Primary Sjögren's Syndrome and Systemic Sclerosis. PLoS One. 2016; 11(7): e0159384.
  22. Widner B, Sepp N, Kowald E, et al. Degradation of tryptophan in patients with systemic lupus erythematosus. Adv Exp Med Biol. 1999; 467: 571–577.
  23. Widner B, Sepp N, Kowald E, et al. Enhanced tryptophan degradation in systemic lupus erythematosus. Immunobiology. 2000; 201(5): 621–630.
  24. Figueiredo-Braga M, Cornaby C, Cortez A, et al. Depression and anxiety in systemic lupus erythematosus: The crosstalk between immunological, clinical, and psychosocial factors. Medicine (Baltimore). 2018; 97(28): e11376.
  25. 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.
  26. Anderson EW, Fishbein J, Hong J, et al. Quinolinic acid, a kynurenine/tryptophan pathway metabolite, associates with impaired cognitive test performance in systemic lupus erythematosus. Lupus Sci Med. 2021; 8(1).
  27. Vogelgesang SA, Heyes MP, West SG, et al. Quinolinic acid in patients with systemic lupus erythematosus and neuropsychiatric manifestations. J Rheumatol. 1996; 23(5): 850–855.
  28. Almaani S, Meara A, Rovin BH. Update on Lupus Nephritis. Clin J Am Soc Nephrol. 2017; 12(5): 825–835.
  29. Markowitz GS, D'Agati VD. Classification of lupus nephritis. Curr Opin Nephrol Hypertens. 2009; 18(3): 220–225.
  30. Lood C, Tydén H, Gullstrand B, et al. Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus. PLoS One. 2015; 10(4): e0125109.
  31. Pawlak K, Myśliwiec M, Pawlak D. Kynurenine pathway - a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients. Adv Med Sci. 2010; 55(2): 196–203.
  32. Anekthanakul K, Manocheewa S, Chienwichai K, et al. Predicting lupus membranous nephritis using reduced picolinic acid to tryptophan ratio as a urinary biomarker. iScience. 2021; 24(11): 103355.
  33. Pertovaara M, Hasan T, Raitala A, et al. Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season. Clin Exp Immunol. 2007; 150(2): 274–278.
  34. Choi SC, Brown J, Gong M, et al. Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice. Sci Transl Med. 2020; 12(551).
  35. Parisis D, Chivasso C, Perret J, et al. Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy. J Clin Med. 2020; 9(7).
  36. Jonsson R, Brokstad KA, Jonsson MV, et al. Current concepts on Sjögren's syndrome - classification criteria and biomarkers. Eur J Oral Sci. 2018; 126 Suppl 1(Suppl Suppl 1): 37–48.
  37. Srivastava A, Makarenkova HP. Innate Immunity and Biological Therapies for the Treatment of Sjögren's Syndrome. Int J Mol Sci. 2020; 21(23).
  38. 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).
  39. Tanaka Y, Onozato M, Mikami T, et al. Increased Indoleamine 2,3-Dioxygenase Levels at the Onset of Sjögren's Syndrome in SATB1-Conditional Knockout Mice. Int J Mol Sci. 2021; 22(18).
  40. Sardenberg WM, Santos MC, Skarstein K, et al. Acinar adipose tissue infiltration in salivary gland biopsy is associated with kynurenines-interferon-γ pathway inflammation biomarkers. Clin Exp Rheumatol J. 2020;38 (4):27-33 PMID; 38(Suppl 126 (4)): 27–33.
  41. Chhadva P, Lee T, Sarantopoulos CD, et al. Human Tear Serotonin Levels Correlate with Symptoms and Signs of Dry Eye. Ophthalmology. 2015; 122(8): 1675–1680.
  42. Imada T, Nakamura S, Hisamura R, et al. Serotonin hormonally regulates lacrimal gland secretory function via the serotonin type 3a receptor. Sci Rep. 2017; 7(1): 6965.
  43. Valim V, Sardemberg WM, Brun JG, et al. Interferon ɣ-inducible kynurenines inflammation pathway: the missing link between disease activity and symptoms in Sjögren’s syndrome. Ann Rheum Dis. 2017; 76: 1102.
  44. Furuzawa-Carballeda J, Lima G, Jakez-Ocampo J, et al. Indoleamine 2,3-dioxygenase-expressing peripheral cells in rheumatoid arthritis and systemic lupus erythematosus: a cross-sectional study. Eur J Clin Invest. 2011; 41(10): 1037–1046.
  45. Maria NI, van Helden-Meeuwsen CG, Brkic Z, et al. Association of Increased Treg Cell Levels With Elevated Indoleamine 2,3-Dioxygenase Activity and an Imbalanced Kynurenine Pathway in Interferon-Positive Primary Sjögren's Syndrome. Arthritis Rheumatol. 2016; 68(7): 1688–1699.
  46. Pertovaara M, Raitala A, Uusitalo H, et al. Mechanisms dependent on tryptophan catabolism regulate immune responses in primary Sjögren's syndrome. Clin Exp Immunol. 2005; 142(1): 155–161.
  47. Furuzawa-Carballeda J, Hernández-Molina G, Lima G, et al. Peripheral regulatory cells immunophenotyping in primary Sjögren's syndrome: a cross-sectional study. Arthritis Res Ther. 2013; 15(3): R68.
  48. Yue EW, Sparks R, Polam P, et al. INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology. ACS Med Chem Lett. 2017; 8(5): 486–491.