The pathogenesis of DLD-mediated cuproptosis induced spinal cord injury and its regulation on immune microenvironment

Chaochen Li; Chunshuai Wu; Chunyan Ji; Guanhua Xu; Jiajia Chen; Jinlong Zhang; Hongxiang Hong; Yang Liu; Zhiming Cui

doi:10.3389/fncel.2023.1132015

The pathogenesis of DLD-mediated cuproptosis induced spinal cord injury and its regulation on immune microenvironment

Front Cell Neurosci. 2023 May 9:17:1132015. doi: 10.3389/fncel.2023.1132015. eCollection 2023.

Authors

Chaochen Li^#^{1

2

3}, Chunshuai Wu^#^{1

2

3}, Chunyan Ji^#^{1

2

3}, Guanhua Xu¹, Jiajia Chen¹, Jinlong Zhang¹, Hongxiang Hong¹, Yang Liu¹, Zhiming Cui^{1

2

3}

Affiliations

¹ The Affiliated Hospital 2 of Nantong University, Nantong University, The First People's Hospital of Nantong, Nantong, China.
² Key Laboratory for Restoration Mechanism and Clinical Translation of Spinal Cord Injury, Nantong, China.
³ Research Institute for Spine and Spinal Cord Disease of Nantong University, Nantong, China.

^# Contributed equally.

Abstract

Introduction: Spinal cord injury (SCI) is a severe central nervous system injury that leads to significant sensory and motor impairment. Copper, an essential trace element in the human body, plays a vital role in various biological functions and is strictly regulated by copper chaperones and transporters. Cuproptosis, a novel type of metal ion-induced cell death, is distinct from iron deprivation. Copper deprivation is closely associated with mitochondrial metabolism and mediated by protein fatty acid acylation.

Methods: In this study, we investigated the effects of cuproptosis-related genes (CRGs) on disease progression and the immune microenvironment in acute spinal cord injury (ASCI) patients. We obtained the gene expression profiles of peripheral blood leukocytes from ASCI patients using the Gene Expression Omnibus (GEO) database. We performed differential gene analysis, constructed protein-protein interaction networks, conducted weighted gene co-expression network analysis (WGCNA), and built a risk model.

Results: Our analysis revealed that dihydrolipoamide dehydrogenase (DLD), a regulator of copper toxicity, was significantly associated with ASCI, and DLD expression was significantly upregulated after ASCI. Furthermore, gene ontology (GO) enrichment analysis and gene set variation analysis (GSVA) showed abnormal activation of metabolism-related processes. Immune infiltration analysis indicated a significant decrease in T cell numbers in ASCI patients, while M2 macrophage numbers were significantly increased and positively correlated with DLD expression.

Discussion: In summary, our study demonstrated that DLD affects the ASCI immune microenvironment by promoting copper toxicity, leading to increased peripheral M2 macrophage polarization and systemic immunosuppression. Thus, DLD has potential as a promising biomarker for ASCI, providing a foundation for future clinical interventions.

Keywords: DLD; cuproptosis; immune microenvironment; machine learning; spinal cord injury (SCI).

Grants and funding

This study was supported by National Natural Science Foundation of China (grant numbers: 81771319 and 82002394), Nantong Health Commission Research Project (grant number: MA2021016), and Medical Research Project of Jiangsu Commission of Health (grant number: ZDB2020004).