Physical inactivity exacerbates pathologic inflammatory signalling at the single cell level in patients with systemic...

Area of Science:

• Immunology
• Rheumatology
• Genomics

Background:

• Physical activity improves symptoms in systemic lupus erythematosus (SLE).
• Mechanisms linking physical activity to SLE symptom improvement are unclear.
• Understanding these mechanisms can optimize therapeutic strategies.

Purpose of the Study:

• To investigate the molecular mechanisms by which physical activity influences immune cell profiles in SLE patients.
• To identify specific immune cell populations and gene expression patterns associated with physical activity levels in SLE.

Main Methods:

• Cohort study of 123 SLE patients from the California Lupus Epidemiology Study (CLUES).
• Assessed self-reported physical activity using a validated instrument.
• Analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data to compare immune cell frequencies, gene expression, and cytokine activation between physically active and inactive patients.

Main Results:

• Sedentary SLE patients showed greater CD4+ T cell lymphopenia.
• Physical inactivity was associated with a distinct transcriptional signature in CD4+ and CD8+ T cells, involving hundreds of differentially expressed genes.
• Gene set enrichment analysis revealed enrichment of pro-inflammatory pathways (TNF-α, IFN-γ, IL2/STAT5, IL6/JAK/STAT3) in physically inactive individuals.
• Computational analysis predicted increased activation of pro-inflammatory cytokines (TNF-α, IFN-γ, IL1β) in CD4+ T cells of inactive patients.

Conclusions:

• Physical inactivity in SLE is mechanistically linked to altered immune cell frequencies and transcriptional profiles.
• Inactivity may exacerbate pathologic inflammation via CD4+ and CD8+ T cells.
• Findings provide a molecular basis for the benefits of physical activity in managing SLE.