Background Systemic Lupus Erythematosus (SLE) is characterized by numerous seemingly unconnected abnormalities. These include: 1) a multisystem inflammatory syndrome, 2) a strong type I Interferon (IFN-I) gene signature in peripheral blood lymphocytes (PBL), 3) an unusual population of CD4-CD8- T-+cells, 4) SLE T cells containing enlarged mitochondria and reactive oxygen species (ROS), and 5) a polymorphism in Mitochondrial antiviral stimulator (MAVS C79F) associated with milder SLE. Our studies provide a unifying model for these abnormalities through augmented T cell homeostatic proliferation, which leads to two parallel cellular pathways: first, progressive upregulation of cytolytic inflammatory molecules, including high levels of Fas-Ligand (FasL), Granzyme B, and IFN-gamma, and second, generation of CD4-CD8- T cells from CD8 +precursors, which manifest disorganized enlarged mitochondria, elevated reactive oxygen species (ROS) that drives oligomerization of MAVS and IFN-I production.
Methods PBL from active SLE patients and age- and sex-matched healthy controls were assessed for increased expression of the T cell homeostatic proliferation phenotype determined from our murine studies: CD45RO+PD-1+SLAMF7+IL-7R-alpha-. The same cells were analyzed for MAVS oligomerization. Young lupus-prone MRL-lpr mice were treated for 11 weeks with the mitochondrially targeted antioxidant MitoQ.
Results Reactive oxygen species (ROS) is sufficient to drive MAVS oligomerization and IFN-I production in cell lines and primary human PBL. However, PBL from SLE patients manifested spontaneous MAVS oligomerization, which paralleled the levels of serum INF-I and SLEDAI score (figure 1). Furthermore, SLE patients had evidence of increased T cell homeostatic proliferation. In addition, SLE patients had evidence of increased I cell homeostatic proliferation, based on increased IL-7R- Ki67 +T cells. Very similar findings were observed in lupus prone MRL-lpr mice. Treatment of MRL-lpr mice over 11 weeks with the mitochondrially-targeted anti-oxidant MitoQ inhibited MAVS oligomerization, reduced serum IFN-I, improved dermatitis, and reduced kidney immune complexes.
Conclusions Conclusions: Human and murine SLE have evidence of mitochondrial dysfunction, elevated ROS, spontaneous MAVS oligomerization and elevated IFN-I, as well as augmented T cell homeostatic proliferation. These abnormalities can be largely reversed with MitoQ, with alleviation of disease in murine SLE.
Funding Source(s): NIH (NIAID, NIAMS, NIGMS)
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