Beyond cell death: novel roles for RIP kinases in cardiometabolic diseases

Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis, obesity and insulin resistance. RIP kinases (RIPK) are a member of serine/threonine family of kinases that have recently been shown to play an important role in cell death. We have previously shown that necroptosis, a pro-inflammatory form for programmed cell death, is activated in the vessel wall and drives atherosclerosis via activation of RIPK3 and its downstream target, MLKL. Here, we sought to determine upstream regulators of necroptosis in atherosclerosis and metabolic disease, and hypothesized that RIPK1, a key regulatory kinase upstream of NF-B activation, apoptosis and necroptosis, drives immune cell inflammation in cardiometabolic diseases. Our studies identify a novel role for RIPK1 beyond its kinase activity, where its gene expression is increased during atherosclerosis and obesity. Importantly, we can therapeutically knockdown RIPK1 to treat atherosclerotic progression and diet-induced obesity in 2 independent mouse models. This seminar will explore the intricate yet distinct mechanisms by which genetic regulation of RIPK1 drives early atherosclerosis and diet-induced obesity.