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

Sarah L Patterson; Hoang Van Phan; Chun Jimmie Ye; Cristina Lanata; Sebastián Cruz González; Joonsuk Park; Lindsey A Criswell; Kamil E Barbour; Jinoos Yazdany; Maria Dall'Era; Marina Sirota; Patricia Katz; Charles R Langelier

doi:10.1016/j.ebiom.2024.105432

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

EBioMedicine. 2024 Nov 11:110:105432. doi: 10.1016/j.ebiom.2024.105432. Online ahead of print.

Affiliations

¹ Division of Rheumatology, University of California, San Francisco, CA, USA. Electronic address: sarah.patterson@ucsf.edu.
² Division of Infectious Diseases, University of California, San Francisco, CA, USA.
³ Division of Rheumatology, University of California, San Francisco, CA, USA.
⁴ National Human Genome Research Institute, Bethesda, MD, USA.
⁵ Department of Epidemiology and Biostatistics, United States of America.
⁶ Centers for Disease Control and Prevention, Atlanta, GA, USA.
⁷ Department of Pediatrics, University of California, San Francisco, CA, USA.
⁸ Division of Infectious Diseases, University of California, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.

PMID: 39531917
DOI: 10.1016/j.ebiom.2024.105432

Abstract

Background: Physical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear.

Methods: We carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race.

Findings: We found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (P_adj = 0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (P_adj < 0.1). Gene set enrichment analysis demonstrated enrichment of proinflammatory genes in the TNF-α signalling through NF-kB, interferon-γ (IFN-γ), IL2/STAT5, and IL6/JAK/STAT3 signalling pathways. Computational prediction of upstream cytokine activation states suggested CD4+ T cells from physically inactive patients exhibited increased activation of TNF-α, IFN-γ, IL1Β, and other proinflammatory cytokines. Network analysis demonstrated interconnectivity of genes driving the proinflammatory state of sedentary patients. Findings were consistent in sensitivity analyses adjusting for corticosteroid treatment and physical function.

Interpretation: Taken together, our findings suggest a mechanistic explanation for the observed benefits of physical activity in patients with SLE. Specifically, we find that physical inactivity is associated with altered frequencies and transcriptional profiles of immune cell populations and may exacerbate pathologic inflammatory signalling via CD4+ and CD8+ T cells.

Funding: This work was supported by the US National Institutes of Health (NIH) (R01 AR069616, K23HL138461-01A1, K23AT011768) the US CDC (U01DP0670), and the CZ Biohub.

Keywords: Lifestyle behaviors; Physical activity; Rheumatoid arthritis; Single cell transcriptomics.