Myeloid STAT4 at the Intersection of Sleep Disruption and Hyperlipidemia: A Molecular Link Between Lifestyle Stress and Atherogenesis 2261152

Abstract

Abstract Introduction Neutrophils, crucial regulators of antimicrobial defense, also play a role in atherosclerosis. STAT4 controls key neutrophil functions, including ROS generation, NETosis, and migration. Myeloid STAT4 deficiency reduces atherogenesis but impairs antimicrobial defense. Sleep fragmentation (SF), a widespread health concern, increases cardiovascular risk. SF accelerates atherosclerosis in a neutrophil-dependent manner by hyperactivating neutrophil functions. Methods To test the role of STAT4 in SF-accelerated atherosclerosis, myeloid-specific STAT4-deficient low-density lipoprotein receptor-deficient Stat4fl/fl LysMcre Ldlr-/- and Stat4fl/fl Ldlr-/- mice were subjected to chronic SF and HFD for 16 weeks. We used Kaplan—Meier analysis to monitor survival, Oil Red O staining to quantify aortic plaque burden and spectral flow cytometry to assess neutrophil effector functions. Intestinal oxidative stress and microbial translocation were evaluated via histology and ELISA. Results Myeloid-specific STAT4 deficiency reduced neutrophil production, activation, and atherosclerosis, but also caused peritonitis and increased mortality after SF and HFD feeding in Stat4fl/flLysMcreLdlr-/- vs Stat4fl/flLdlr-/- mice. Premature death was linked to peritonitis, possibly due to intestinal inflammation and barrier dysfunction. Conclusion Thus, STAT4 critically balances immune responses during sleep fragmentation by driving inflammatory neutrophil activation that promotes atherosclerosis while simultaneously preserving essential host defense mechanisms, underscoring its dual role in modulating inflammation and survival under physiological stress. Funding Source AHA Predoctoral Fellowship Grant, AHA Innovation Grant Topic Categories Immune Mechanisms of Human Disease (HUM)