Post Doctoral Researcher Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Virginia, United States
Disclosure(s):
Alina Moriarty: No financial relationships to disclose
Introduction/Rationale: 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/flLysMcreLdlr-/- and Stat4fl/flLdlr-/- 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.
