The Defect of iNKT Cells Mediates Mitochondrial Dysfunction Through IL-6/STAT3 Signaling to Induce Atrial...

Atrial inflammation and fibrosis are the pathogenesis of postoperative atrial fibrillation (POAF). It has been reported that invariant natural killer T (iNKT) cells can coordinate tissue inflammation, but whether it can regulate POAF is still unknown. A sterile pericarditis (SP) model was constructed on C57BL/6J mice and Jalpha18-/- mice to simulate POAF. Intraperitoneal injection of anti-interleukin (IL) -6 neutralizing antibody (anti-IL-6) was used for intervention, and atrial fibrillation (AF) was induced by transesophageal sinus atrial node pulse pacing. The levels of iNKT cells and IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway were detected by flow cytometry and western blot. HE stain, Masson stain, and immunohistochemistry were used to evaluate the process of inflammation and fibrosis in atrial tissue. The calcium homeostasis and function of atrial mitochondria were evaluated by biochemical detection and fluorescent staining. The expression of iNKT cells was up-regulated in SP mice. The defect of iNKT cells increased the AF induction rate and duration of SP mice, enhanced AF susceptibility, aggravated atrial electrical remodeling, promoted inflammatory cell infiltration and fibrosis, and increased inflammatory factors and fibrotic proteins. Compared with SP mice, iNKT cell defects also aggravated endoplasmic reticulum-mitochondrial calcium coupling disorder, mitochondrial calcium homeostasis imbalance, reduced mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) content, and mitochondrial complex enzyme activity, and increased IL-6 and STAT3 phosphorylation levels. Anti-IL-6 significantly inhibited IL-6/STAT3 signaling pathway, reduced AF induction rate and duration, and improved atrial mitochondrial calcium homeostasis, mitochondrial dysfunction, inflammation, and fibrosis. The deficiency of iNKT cells aggravated atrial tissue mitochondrial dysfunction, inflammation, and fibrosis in POAF mice via activating IL-6/STAT3 axis, and aggravated AF susceptibility.