Unveiling the role of abnormal copper metabolism in systemic lupus erythematosus
Zigu Chen1, Shaowei Yan1, Chuiwen Deng2
1State Key Laboratory of Environmental Chemistry and Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100190, China.
Objective:
Metabolic dysregulation is increasingly implicated in systemic lupus erythematosus (SLE). Given the crucial role of copper (Cu) in immunity, its specific metabolic alterations in SLE remain poorly understood. By integrating cross-sectional exploratory research, transcriptomic analysis, and murine experiments, this study aims to investigate the phenotypic signatures of aberrant Cu metabolism in SLE, alongside its molecular mechanisms and therapeutic potential.
Methods:
In blood samples from patients and healthy controls, Cu concentrations and stable isotopic ratios (δ65Cu) were measured using inductively coupled plasma mass spectrometry (ICP-MS) and multi-collector ICP-MS, respectively. To explore the mechanisms, molecular alterations were assessed using publicly available blood transcriptomic datasets and Western blotting. The effects of Cu modulation on disease progression were further evaluated in lupus-prone MRL/lpr mice treated with the Cu chelator ammonium tetrathiomolybdate (TTM). Statistical analyses included between-group comparisons, analysis of covariance and multivariable logistic regression for confounder adjustment, association analyses, and gene set enrichment analyses.
Results:
Autoimmune disease patients (n = 50), particularly SLE patients (n = 21), exhibited distinct Cu metabolic profiles compared to healthy controls (n = 34), with elevated plasma Cu concentration (mean 1.38 [95% CI 1.21-1.56] vs 1.20 [95% CI 1.13-1.28] μg/g; P = 0.058) but decreased δ65Cu in both plasma (mean -0.33‰ [95% CI -0.45‰--0.21‰] vs -0.05‰ [95% CI -0.13‰-0.03‰]; P < 0.0001) and blood cells (mean 0.23‰ [95% CI 0.09‰-0.38‰] vs 0.98‰ [95% CI 0.88‰-1.09‰]; P < 0.0001). Key Cu buffering (albumin, ceruloplasmin) and transport (STEAP4) proteins were dysregulated in SLE. Blood transcriptome analysis of SLE patients (n = 264) and healthy subjects (n = 83) from a public database revealed multiple dysregulated genes in Cu metabolism, which were associated with Cu uptake/efflux and pathways related to mitochondrial respiration and collagen cross-linking. In the MRL/lpr mice, limiting Cu bioavailability via TTM alleviated disease severity, reducing lymphadenopathy and kidney inflammation and fibrosis.
Conclusion:
We highlighted Cu metabolism abnormalities in SLE, proposing blood cell δ65Cu as a potential exploratory biomarker. Aberrant Cu metabolism may contribute to SLE pathology, potentially through mitochondrial and collagen-related pathways, and could be modulated by Cu chelation, suggesting a novel perspective for therapeutic intervention in SLE.
