Macrophage retrotransposon expression is associated with lupus

Genetic variants of NCF1 that impair the production of reactive oxygen species (ROS) are associated with lupus in humans; however, the underlying mechanism of immune dysregulation remains unclear. To clarify this mechanism, the study tested the hypothesis that retrotransposons contribute to the early onset of lupus by facilitating the expansion and activation of macrophages. Using the ROS-deficient lupus-prone lpr mouse model, we employed bulk RNA sequencing, flow cytometry, and spatially resolved single-cell transcriptome imaging to comprehensively characterize tissue-resident macrophages. The results demonstrated increased expression of the mouse transcript family type D (MTD) retrotransposon in tissue-resident macrophages from the spleen, kidneys, and skull dura of ROS-deficient lpr mice, indicating a link between ROS deficiency, MTD expression, and macrophage expansion. Importantly, this MTD expression decreased following two weeks of mycophenolate mofetil therapy, linking therapy response to retrotransposon activity. Furthermore, the MTD-encoded RNA was used to disrupt the signaling of retrotransposons, leading to regulatory T-cell activation and downregulation of both glomerular macrophage infiltration and serum interleukin-6 secretion in lupus-prone mice. Collectively, these findings suggest that the MTD retrotransposons play a crucial role in driving the early onset of lupus by enhancing macrophage activation, which in turn promotes immune dysregulation.