Dual Role of IgA in Gut Integrity and Pro-Inflammatory Activation During Atherogenesis and Sleep Fragmentation 2261038

Introduction Atherosclerosis is a chronic disease involving immune dysregulation and the formation of dangerous plaque in vessels. IgA maintains gut homeostasis but may also contribute to inflammation in the circulation under pathological conditions. Sleep fragmentation (SF), common in modern life, exacerbates systemic inflammation and atherosclerosis. To date, the role of IgA in atherogenesis and in SF-accelerated atherosclerosis is unclear. Methods To test the role of SF on mucosal immunity in atherosclerosis, Apolipoprotein E-deficient (Apoe-/-) mice were fed a high-fat diet (HFD) and placed on an SF or activity control regimen for 12 weeks. We tested the role of IgA on macrophage phenotype and foam cell formation, in vitro. Finally, to test the role of IgA in atherogenesis, we generated atherosclerosis-prone IgA-deficient low-density lipoprotein receptor-deficient Iga-/-Ldlr-/- mice and placed them on HFD feeding for 12 weeks. Results SF promoted atherosclerosis in HFD-fed Apoe-/- mice. SF also elevated intestinal reactive oxygen species (ROS) and IFNγ, and significantly reduced IgA+ B cell frequency and tight junction protein expression in the gut of HFD-fed SF vs AC Apoe-/- mice.12 wks HFD-fed Iga-/-Ldlr-/- mice showed attenuated plaque burden and reduced leukocyte infiltration into the aorta vs HFD-fed Ldlr-/- controls. IgA binds to pathogenic oxidized LDL (oxLDL) and thus may potentially reduce foam cell formation. In vitro, mouse and human IgA, when co-incubated with oxLDL, reduced oxLDL uptake by macrophages but enhanced their activation and ROS, suggesting a pro-inflammatory role of IgA in the circulation.Thus, IgA plays a paradoxical role in SF-accelerated atherosclerosis, preserving gut barrier integrity while promoting pro-inflammatory myeloid activation. Conclusion These findings suggest IgA as a key immunomodulator at the interface of mucosal immunity and vascular inflammation.