Chronic sleep deprivation promotes atherosclerosis via NFIL3/RORγt Axis mediated Th17/Treg imbalance, targeting IL-17A attenuates disease progression

Background Chronic sleep deprivation (CSD) is an independent risk factor for atherosclerotic cardiovascular disease, but the underlying mechanisms remain elusive. This study aimed to investigate whether CSD accelerates atherosclerosis by disrupting Th17/Treg balance and to explore a potential immunotherapeutic strategy. Methods Low-density lipoprotein receptor-deficient ( Ldlr −/− ) mice were subjected to CSD or non-chronic sleep deprivation (NSD) for 12 weeks alongside a Western-type diet. Atherosclerotic plaque burden and stability were assessed histologically. Immune profiling was performed by flow cytometry. Transcriptomic analysis (RNA-seq) revealed signaling pathways perturbed by CSD. Naïve CD4 + T cells from CSD and NSD mice were polarized to Th17 cells in vitro; their conditioned medium was applied to mouse aortic endothelial cells (MAECs) to evaluate apoptosis and inflammatory activation. The role of IL-17A was tested by in vitro neutralization and in vivo administration of an anti-IL-17A monoclonal antibody. Key regulatory molecules were examined by siRNA knockdown and immunoblotting. Results CSD markedly exacerbated atherosclerotic plaque progression and instability, concurrent with a heightened Th17/Treg ratio. Mechanistically, CSD downregulated the circadian transcription factor NFIL3 in CD4 + T cells, leading to derepression of RORγt and driving pathogenic Th17 cell differentiation. Conditioned medium from CSD-derived Th17 cells markedly induced apoptosis and inflammatory activation in MAECs, effects that were attenuated by IL-17A neutralization in vitro. Crucially, in vivo IL-17A neutralization attenuated CSD-accelerated atherosclerosis, reduced endothelial inflammation, and thus validated its role as a key therapeutic target. Conclusion Our study demonstrates that chronic sleep deprivation promotes atherosclerosis via an NFIL3/RORγt axis-mediated Th17/Treg imbalance. Targeting the downstream effector IL-17A represents a viable therapeutic strategy. These findings establish a novel immune mechanism linking sleep disruption to cardiovascular disease and highlight the therapeutic promise of targeting IL-17A.