Immune mitochondrial complex I mediates vascular damage in toll-like receptor 7 (TLR7)-induced lupus.

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and high cardiovascular risk, including hypertension and endothelial dysfunction. Metabolic reprogramming of immune cells, particularly CD4 + T cells, contributes to SLE pathogenesis. We investigated the role of mitochondrial metabolism, specifically the NDUFS4 subunit of complex I, in immune cells during lupus induced by toll-like receptor (TLR)7 activation with imiquimod (IMQ). We analyzed transcriptomic data from peripheral blood mononuclear cells obtained from SLE patients and their matched healthy controls showing that dendritic cells and undetermined cells exhibited the highest mean expression levels of NDUFS4. Using bone marrow chimeric mice, we demonstrate that NDUFS4 deficiency in hematopoietic cells prevents IMQ-induced hypertension, reduces autoantibody production, and limits vascular oxidative stress, inflammation, and kidney injury. These effects are associated with a shift in CD4 + T cell polarization toward regulatory T cells and a reduction in Th1 and Th17 subsets in the spleen and blood. Pharmacological dual inhibition of glycolysis with 2-deoxy-D-glucose and mitochondrial metabolism with metformin further supports the therapeutic potential of metabolic targeting, improving vascular function and preventing aortic remodeling, characterized by proteoglycan and collagen accumulation, increased aortic stiffness, and secretory and profibrotic phenotypes. These interventions reduce oxidative stress and immune cell infiltration in the vascular wall, mitigating endothelial dysfunction and the shift to a synthetic phenotype. Our findings highlight mitochondrial complex I as a critical modulator of immune-mediated vascular damage in lupus induced by TLR7 activation and propose metabolic reprogramming as a promising therapeutic strategy for lupus-associated cardiovascular complications.