Fig. 4

Persistent IL-1 production drives the pathogenesis of sterile chronic inflammatory diseases. Persistent IL-1 production sustains the vicious cycle between metabolic stress and chronic inflammation, driving the pathogenesis of chronic inflammatory diseases such as cardiovascular diseases, type 2 diabetes, and nonalcoholic fatty liver disease. Metabolic stressors activate the inflammasome, resulting in increased levels of IL-1 that perpetuate chronic inflammation. This mechanism is central to the generation, progression, and eventual rupture of atherosclerotic plaques. Oxidized low-density lipoprotein (OxLDL) and cholesterol crystals accumulate in macrophages within arteries, promoting foam cell formation and inflammasome activation. This results in IL-1 production, which in turn leads to the activation of endothelial cells, further recruitment of leukocytes, and vascular smooth muscle cell proliferation, inducing plaque growth. Additionally, it promotes the production of matrix metalloproteinases (MMPs), which, by weakening the fibrous cap of the plaque, increase the risk of plaque rupture and thrombosis. Ultimately, atherosclerosis predisposes patients to cardiovascular diseases. Inflammaging and obesity lead to a chronic increase in IL-1 production. Persistent IL-1 impairs glucose metabolism by disrupting insulin signaling, reducing insulin receptor substrate 1 (IRS-1) phosphorylation, inducing pancreatic β-apoptosis and impairing the differentiation of adipocytes. Through these mechanisms, chronic IL-1 elevation can promote insulin resistance and the development of type 2 diabetes. Chronically elevated IL-1 levels also induce hepatic lipogenesis, predisposing patients to nonalcoholic fatty liver disease (NAFLD). Insulin resistance exacerbates this condition by further stimulating lipid accumulation in the liver. Insulin resistance, type 2 diabetes, NAFLD, atherosclerosis, and cardiovascular diseases are closely related. Insulin resistance promotes vascular damage by inducing endothelial dysfunction and inflammation. Conversely, atherosclerosis increases systemic inflammation, which worsens glucose metabolism and further exacerbates insulin resistance. Moreover, insulin resistance-driven hepatic lipogenesis worsens NAFLD, with downstream effects on lipid metabolism and cardiovascular risk