Systemic lupus erythematosus (SLE) is an autoimmune disease marked by premature atherosclerosis and thrombotic complications. The increased levels of interferon(IFN)α observed in SLE amplify cardiovascular and thrombotic risks. Thus, these patients are confronted with a double burden, where systemic inflammation not only contributes to an increased risk of cardiovascular diseases (CVD) but also exacerbates the propensity for clotting, creating a vicious cycle that amplifies both risks and complications in SLE.
The long-term goal of this project is to identify mechanisms driving endothelial damage and thromboinflammation in SLE. The central hypothesis, based on preliminary data, suggests that IFNα-driven aberrant activation of low-density neutrophils (LDNs), normal-density neutrophils(NDNs), and macrophages lead to endothelial damage and a hypercoagulable state through altered metabolism. The project’s objectives are (1) to identify distinct metabolic and inflammatory profiles in SLE-derived LDNs and monocytes, (2) to evaluate the role of metabolic reprogramming in blood coagulation, and (3) to elucidate immune pathways linked to thromboinflammation in SLE. This study is innovative in its (a) interdisciplinary approach to dissecting metabolic reprogramming, inflammation, and coagulation in SLE and (b) introduces a novel concept that endothelial damage and thrombosis in SLE are intricately linked to metabolic alterations in LDNs,NDNs, and macrophages, which have not yet been investigated.It holds significance in identifying new therapeutic targets and providing a model approach for understanding complex interplays in autoimmune diseases, potentially applicable to chronic inflammatory conditions.
The expected outcomes of this research encompass a step forward in treating immunothrombotic phenomenon in SLE, with a specific emphasis on cell-mediated mechanisms and their role in clotting, as well as integrated omics to inform clotting-specific signatures.This research is expected to drive future clinical practices through actionable knowledge, leading to treatment strategies for managing SLE and its associated thrombotic complications which are currently lacking in the Republic of Ireland and world-wide.