The pathogenesis of autoimmune conditions is known to be significantly influenced by both macrophage dysregulation and mitochondrial malfunction. Nevertheless, the precise pathways that couple these two elements remain inadequately defined. We propose in this study that a sustained, low-grade presence of interferon-gamma (IFN-γ) acts as a pivotal mediator in these events. To examine this, experiments were conducted using ARE-Del mice, a strain that displays enduring, low-level IFN-γ production alongside features characteristic of lupus nephritis (LN). Investigation of gene expression as a function of age and tissue type in these mice revealed pronounced downregulation of mitochondrial complex I subunits and their associated functions, particularly in renal tissue. The suppression of mitochondrial complex I linked to the mouse genotype signifies an initial defect that precipitates macrophage dysfunction. Of particular interest, the induction of remission in NZB/W lupus-prone mice led to a recovery of mitochondrial complex I gene expression and a correction of macrophage dysfunction in kidney-derived macrophages. Collectively, these observations imply that sustained, low-concentration IFN-γ impairs mitochondrial complex I function in macrophages, underscoring its role in the incipient stages of autoimmune disorders such as lupus nephritis. This work yields a novel understanding of the molecular dialogues that are fundamental to autoimmune development and points toward possible therapeutic entry points.
