Interferon-Driven Tryptophan Metabolism Links Inflammation and Mental Health in Juvenile Dermatomyositis
Yang Wu1,2, Aviya L Levy3,4, Payton Hermanson2
1Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
Insights
Juvenile dermatomyositis (JDM) involves altered tryptophan metabolism, increasing kynurenine pathway products linked to inflammation and mental health issues. Targeting this pathway may improve JDM outcomes.
Area of Science:
- Immunology
- Neuroscience
- Pediatrics
Background:
- Juvenile dermatomyositis (JDM) is associated with significant mental health challenges like anxiety and depression.
- Inflammation in JDM can disrupt tryptophan metabolism via the indoleamine 2,3-dioxygenase (IDO) kynurenine pathway, similar to mood disorders.
Purpose of the Study:
- To investigate the association between skewed tryptophan metabolism, disease activity, and mental health symptoms in JDM.
- To explore the role of interferon (IFN) in JDM pathogenesis and its impact on tryptophan metabolism.
Main Methods:
- Serum samples from JDM patients, juvenile idiopathic arthritis patients, and healthy controls were analyzed for tryptophan metabolites.
- Interferon-regulated genes were measured, and the ability of serum to induce IDO was assessed.
- Cluster analysis identified clinical subgroups within the JDM cohort.
Main Results:
- JDM patients exhibited lower tryptophan and serotonin, but higher kynurenine pathway metabolites compared to controls.
- Kynurenine pathway metabolites correlated with muscle inflammation, mental health scores, and disease progression.
- IFN-dependent mechanisms in JDM serum induced IDO, which was inhibited by baricitinib and anifrolumab.
Conclusions:
- Interferon plays a key role in JDM, upregulating IDO and shifting tryptophan metabolism toward the kynurenine pathway.
- This metabolic shift may contribute to poor mental well-being and disease progression in JDM.
- Targeting the IDO kynurenine pathway presents a potential therapeutic strategy for JDM activity and psychological symptoms.
Abstract:
BACKGROUND: Children with juvenile dermatomyositis (JDM) experience significant mental health burdens, including anxiety and depression. Inflammatory activation can alter tryptophan metabolism, particularly through IDO-driven kynurenine pathway induction, which has been implicated in diseases such as mood disorders and SLE. We therefore investigated skewed tryptophan metabolism and its association with disease activity and mental health symptoms in JDM. METHODS: Serum samples from JDM, juvenile idiopathic arthritis (JIA), and healthy controls (HC) were analysed for tryptophan metabolites by ELISA. Interferon-regulated genes were measured using qPCR. Ability of serum to induce indoleamine 2,3-dioxygenase (IDO) was assessed by flow cytometry in presence or absence of interferon antagonists. Cluster analysis was used to identify subgroups. RESULTS: In JDM patients, serum tryptophan and serotonin levels were lower, while kynurenine/tryptophan ratios, kynurenic acid, and quinolinic acid levels were higher compared to healthy controls. Metabolites from the kynurenine pathway were correlated with muscle inflammation (CRP, ESR, aldolase and CK), mental health outcomes (PSC-17 and PHQ-9 scores) and disease progression (PGA scores). Further, IDO1 mRNA levels correlated inversely with serotonin levels and positively with type I interferon signature marker MX2 in PBMCs. Serum from JDM patients induced IDO protein expression in monocytes through an IFN-dependent mechanism, which was significantly inhibited by both baricitinib and anifrolumab. Four clinical subgroups were identified. CONCLUSIONS: Our study reveals a novel role of IFN in JDM pathogenesis, specifically in the upregulation of IDO and subsequent skewing of tryptophan metabolism towards kynurenine pathway, which may correspond to poor mental well-being and disease progression. Targeting this pathway may offer therapeutic potential for both disease activity and psychological outcomes for JDM children.
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