ANK2-MAVS signaling dysfunction triggers mitochondrial stress and enhances IL-8 mediated inflammatory responses in...

Childhood-onset Takayasu arteritis (c-TA) is a severe autoimmune vasculitis with elusive genetic drivers. In this study, the clinical data indicated that c-TA patients exhibited more severe renal stenosis than adult-onset TA (a-TA) patients. Furthermore, whole-exome sequencing of 25 c-TA patients identified two ultra-rare ANK2 gene variants (p.L251I and p.P1306S) in individuals with aggressive renal artery stenosis. Functional studies using ANK2-knockdown models revealed that ANK2 deficiency induces mitochondrial cristae disorganization and membrane hyperpolarization, leading to bioenergetic stress. Integrated multi-omics analyses (RNA-seq, proteomics, metabolomics, and ATAC-seq) demonstrated that ANK2 depletion activates the mitochondrial-immune hub mitochondrial antiviral-signaling protein (MAVS), with MAVS oligomerization markedly enhancing IL-6/IL-8 secretion. Validation in an independent a-TA cohort (n = 131) showed elevated serum IL-8 levels were positively correlated with increased renal stenosis risk, potentially through induction of endothelial barrier dysfunction. Collectively, these findings establish the ANK2-MAVS-IL-8 axis as a critical pathway connecting mitochondrial bioenergetic stress to vascular inflammation. Importantly, IL-8 emerges as a potential biomarker for severe renal stenosis in a-TA, bridging pediatric genetic defects to adult vascular pathology.