Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Genetic risk variants for systemic sclerosis (SSc) are known, but the specific cells involved remain unclear.
• Innate immune cells are proposed SSc targets, yet their effector roles require comprehensive validation.
• This study investigates the role of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc.

Purpose of the Study:

• To elucidate the effector cell role of MDMs in SSc pathogenesis.
• To investigate how genetic variants contribute to SSc susceptibility via MDMs.
• To identify molecular pathways altered in SSc macrophages.

Main Methods:

• RNA sequencing and genome-wide genotyping were performed on MDMs from SSc patients and controls.
• Differential gene expression and expression quantitative trait locus (eQTL) analyses were conducted.
• Integrated analysis with epigenetic, expression, and eQTL data from various immune cells and skin.

Main Results:

• 602 differentially expressed genes were identified in SSc macrophages, enriched for known SSc susceptibility genes.
• GSDMA, carrying an SSc risk variant, was upregulated in SSc MDMs and showed significant eQTL effects in macrophages.
• SSc macrophages exhibited upregulated glycolysis, hypoxia, and mTOR signaling, with downregulated IFNγ response pathways.

Conclusions:

• Macrophages are established as key players in SSc pathogenesis.
• The SSc risk variant rs3894194 likely contributes to susceptibility through GSDMA expression in macrophages.
• MDMs present a distinct transcriptome signature relevant to SSc.