{
  "abstract": "Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis affecting the skin and internal organs. Genetic and environmental factors trigger an aberrant immune response, leading to SSc-specific pathological features. Tryptophan (Trp), an essential amino acid, is crucial for protein synthesis, and its metabolites are involved in diverse physiological processes, including immune regulation and maintenance of organ function. While dysregulated Trp metabolism has been documented in various autoimmune diseases, its comprehensive analysis in SSc remains limited.Material and Methods We developed a novel system to extensively assess Trp metabolites with Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Using this system, we quantified these metabolites in the sera obtained from SSc patients and healthy controls (HCs), and analyzed the correlation with key clinical parameters of SSc. Further, to elucidate the expression of enzymes involved in the Trp metabolism in the skin, we analyzed bulk RNA-sequencing data from skin tissues of patients and HCs, and conducted immunohistochemistry of key metabolic enzymes.Results We found significantly lower Trp and higher kynurenine (Kyn) levels in the sera of SSc patients compared to HCs. Among diffuse cutaneous (dc)SSc patients, serum levels of 3-hydroxykynurenine (3-HK) and the Kyn/Trp ratio strongly correlated with the modified Rodnan total skin thickness score (mRSS). In addition, 3-HK levels were negatively correlated with percent predicted forced vital capacity (%FVC). In line with these changes at the systemic level, analysis of bulk RNA-sequencing data from skin tissues of patients and HCs revealed significantly enhanced expression of the Trp-to-Kyn-converting enzymes IDO1 and TDO2 in SSc. Immunohistochemistry confirmed markedly elevated expression of both enzymes in dermal fibroblasts of SSc patients.Conclusions These findings collectively suggest that dysregulated Trp metabolism contributes to the multifaceted organ involvement and especially to the fibrosis in SSc. Further, given the strong correlation between key clinical parameters and several Trp metabolites, these molecules could potentially serve as good biomarkers for disease activity in SSc.",
  "authors": [
    {
      "affiliations": [
        "Tohoku University Graduate School of Medicine, Department of Dermatology, Sendai, Japan"
      ],
      "name": "Takehiro Takahashi"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Medicine, Department of Dermatology, Sendai, Japan"
      ],
      "name": "Takuya Takahashi"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan"
      ],
      "name": "Masahiro Watanabe"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Medicine, Department of Dermatology, Sendai, Japan"
      ],
      "name": "Yuichiro Segawa"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Medicine, Department of Dermatology, Sendai, Japan"
      ],
      "name": "Kenta Oka"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Medicine, Department of Dermatology, Sendai, Japan"
      ],
      "name": "Toshiya Takahashi"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan",
        "Tohoku University Hospital, Department of Pharmaceutical Sciences, Sendai, Japan"
      ],
      "name": "Masamitsu Maekawa"
    },
    {
      "affiliations": [
        "Tohoku University Graduate School of Medicine, Department of Dermatology, Sendai, Japan"
      ],
      "name": "Yoshihide Asano"
    }
  ],
  "title": "P.016 Tryptophan metabolism dysregulation and its pathogenic roles in systemic sclerosis",
  "uid": "8504d309-6231-51ac-a621-2adfbb44ebd2"
}