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

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

Christian Lood  1 , Helena Tydén  1 , Birgitta Gullstrand  2 , Cecilia Klint  3 , Christina Wenglén  3 , Christoffer T Nielsen  4 , Niels H H Heegaard  4 , Andreas Jönsen  1 , Robin Kahn  5 , Anders A Bengtsson  1
Affiliations

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

Christian Lood et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: CW and CK are employees of AnaMar AB, a Swedish biopharmaceutical company, aiming at developing serotonin receptor antagonists for treatment of inflammatory diseases. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Summarizing figure of the main results and possible hypothesis.
Nucleic acid-containing immune complexes (IC) are phagocytosed by plasmacytoid dendritic cells (pDC) and induce large amounts of interferon (IFN)-alpha. IFN-alpha up-regulates the expression of indoleamine 2,3-dioxygenase (IDO), increasing the conversion of tryptophan to kynurenine and limiting the availability of tryptophan for serotonin synthesis. The produced serotonin is taken up by the platelet close to the enterochromaffin cells. Upon platelet activation, serotonin is released and consumed by immune cells to amplify the inflammatory environment together with ICs and IFN-alpha.
Fig 2
Fig 2. Serotonin levels in platelets and serum are dysregulated in SLE patients.
A) Platelet intracellular serotonin concentration was analyzed by flow cytometry in a subset of the SLE patients and healthy volunteers (HV). B) Correlation analysis for serum and platelet levels of serotonin in SLE patients. C) Treatment with selective serotonin re-uptake inhibitors was associated with decreased serum levels of serotonin in both SLE-patients and HV. D) Serum concentrations of serotonin in HV and SLE patients. The bars represent the median value.
Fig 3
Fig 3. Dysregulated tryptophan metabolism in SLE patients.
A) The activity of the enzyme indoleamine 2,3-dioxygenase (IDO) was indirectly measured as the ratio between kynurenine and tryptophan. The levels of B) tryptophan and C) kynurenine were measured by liquid chromatography.
Fig 4
Fig 4. SLE sera increase IDO expression in a type I IFN-dependent manner.
Endothelial cells (WISH cells) were incubated with A) recombinant IFN-alpha with or without pre-incubation with an IFN alpha/beta receptor blocking antibody (IFNAR ab) and IDO expression analyzed in permeabilized cells by flow cytometry. B) WISH cells were incubated with serum from SLE patients or healthy individuals with or without pre-incubation with an IFNAR ab. The results are presented as percentage increased IDO expression in median fluorescence intensity (MFI) as compared to non-stimulated cells. C) Patients with ongoing type I IFN activity (SLE IFN+) had increased IDO activity as compared to patients with no type I IFN activity (SLE IFN-) and healthy volunteers (HV). D) Patients with ongoing type I IFN activity had decreased serotonin levels as compared to patients with no type I IFN activity and healthy volunteers.
Fig 5
Fig 5. Decreased platelet serotonin levels are associated with platelet activation.
A) Serotonin levels were analyzed in EDTA plasma samples and compared between healthy volunteers (HV) and SLE patients. B) To adjust for differences in total serotonin levels, the relative amount of peripheral versus total serotonin was calculated and compared between HV and SLE patients. SLE patients with a high relative amount of peripheral serotonin (high) was compared to SLE patients with low relative amount of peripheral serotonin levels (low) with regard to C) platelet intracellular serotonin levels, D) serum levels of serotonin, E) platelet microparticle (PMP) count in plasma and F) platelet activation assessed by platelet C4d deposition analyzed by flow cytometry.
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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.