Macrophage retrotransposon expression is associated with lupus

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Genetic variants in NCF1 impairing reactive oxygen species (ROS) production are linked to human lupus.
• The precise mechanisms driving immune dysregulation in lupus remain incompletely understood.

Purpose of the Study:

• To investigate the role of retrotransposons in the early onset of lupus.
• To test the hypothesis that retrotransposons facilitate macrophage expansion and activation in lupus.

Main Methods:

• Utilized ROS-deficient lupus-prone lpr mouse models.
• Employed bulk RNA sequencing, flow cytometry, and single-cell transcriptome imaging.
• Analyzed tissue-resident macrophages from spleen, kidneys, and skull dura.

Main Results:

• Increased expression of mouse transcript family type D (MTD) retrotransposons observed in macrophages of ROS-deficient mice.
• MTD expression decreased with mycophenolate mofetil therapy, correlating therapy response with retrotransposon activity.
• Disruption of MTD retrotransposon signaling led to regulatory T-cell activation and reduced macrophage infiltration and IL-6 secretion.

Conclusions:

• MTD retrotransposons are implicated in the early pathogenesis of lupus.
• Enhanced macrophage activation driven by MTD retrotransposons contributes to immune dysregulation in lupus.
• Targeting MTD retrotransposons may offer a therapeutic strategy for lupus.