Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus

PLoS One. 2015 Apr 21;10(4):e0125109. doi: 10.1371/journal.pone.0125109. eCollection 2015.

Abstract

Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (p<0.0001) as compared to healthy individuals. SLE patients with ongoing type I IFN activity, as determined by an in-house reporter assay, had decreased serum levels of serotonin (p=0.0008) as well as increased IDO activity (p<0.0001), as determined by the kynurenine/tryptophan ratio measured by liquid chromatography. Furthermore, SLE sera induced IDO expression in WISH cells in a type I IFN-dependent manner (p=0.008). Also platelet activation contributed to reduce overall availability of serotonin levels in platelets and serum (p<0.05). Decreased serum serotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Antinuclear / blood
  • Blood Platelets / immunology
  • Blood Platelets / metabolism
  • Blood Platelets / pathology
  • Case-Control Studies
  • Female
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / blood*
  • Interferon Type I / blood*
  • Kidney / immunology
  • Kidney / metabolism*
  • Kidney / pathology
  • Kynurenine / blood
  • Lupus Erythematosus, Systemic / blood*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Male
  • Middle Aged
  • Phenotype
  • Serotonin / biosynthesis*
  • Serotonin / blood
  • Severity of Illness Index
  • Tryptophan / blood

Substances

  • Antibodies, Antinuclear
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interferon Type I
  • Serotonin
  • Kynurenine
  • Tryptophan

Grants and funding

The study was supported by grants from the Medical Faculty at Lund University, The Crafoord Foundation, Greta and Johan Kock’s Foundation, King Gustaf V’s 80th Birthday Foundation, Lund University Hospital, the Swedish Rheumatism Association, Swedish Society of Medicine, the Foundation of the National Board of Health and Welfare and Österlund’s Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. CKL, CWE contributed to the design of the study and to the preparation of the manuscript. The collaboration was purely scientific and focused on basic science related to disease mechanisms. AnaMar did not provide support in the form of salaries for authors others then its employees (CKL and CWE). The specific roles of these authors are articulated in the ‘author contributions’ section. There were no AnaMar compounds involved in the study and AnaMar has no current interest in SLE.