Peripheral HMGB1 Downregulation Is Associated With the S100-IL-17 Axis in Parkinson's Disease: An Integrated Bulk and Single-Cell Transcriptomic Analysis.

Abstract

Background: Accumulating evidence implicates peripheral immune dysregulation in the pathogenesis of Parkinson's disease (PD). High-mobility group box 1 (HMGB1), a key alarmin released during mitochondrial stress, has been reported to be upregulated in the peripheral blood of PD patients, yet its precise role remains unclear.

Methods: We performed an integrated analysis of multiple transcriptomic datasets from peripheral blood mononuclear cells (PBMCs) of PD patients. Using a combination of methods including machine learning, cell-cell communication analysis, in silico gene perturbation, and pathway enrichment analysis, we systematically investigated the expression and regulation of HMGB1 in peripheral immune cells in PD.

Results: We found that HMGB1 mRNA expression was significantly downregulated in PBMCs from PD patients. A machine learning model identified HMGB1 as a potential predictive signature (AUC = 0.685). Single-cell transcriptomic analysis revealed immune cell heterogeneity and identified CD8⁺ T and CD4⁺ T cells as central hubs in the cellular communication network. In silico perturbation analysis suggested that HMGB1 may be associated with the expression of S100A8 and S100A9, which are enriched in the IL-17 signaling pathway. Drug enrichment analysis identified potential therapeutic agents, including TPEN, hydrocotarnine, and phorbol 12-myristate 13-acetate.

Conclusion: Our analysis revealed a distinct downregulation of HMGB1 within the peripheral immune compartment of PD, a change that was decoupled from the overall proinflammatory state. Observing the concomitant upregulation of the S100 gene family and activation of the IL-17 pathway, we propose a putative pathogenic axis based on computational findings: HMGB1 downregulation is linked to S100 gene family upregulation and IL-17 pathway activation.