Cardiovascular diseases (CVDs) remain the leading cause of death and are often the result of progressive atherosclerosis – a chronic inflammatory condition arising from the accumulation and modification of cholesterol-rich low-density lipoproteins (LDL) within arterial walls. Current therapies primarily focus on lowering LDL levels, yet even after reaching target values, many patients remain at high risk of cardiovascular events due to residual inflammation that sustains disease progression.
Key Players in Atherosclerotic Inflammation – Innate Immune Cells: Monocytes, Macrophages, and Neutrophils
Macrophages recognize and clear oxidized LDL and cholesterol crystals, which activate the intracellular signaling complex NLRP3 inflammasome, leading to the release of pro-inflammatory cytokines IL-1β and IL-6.
Neutrophils also contribute to plaque inflammation by releasing reactive oxygen species (ROS), extracellular traps, and enzymes that activate neighboring immune and endothelial cells, damaging the vascular wall and facilitating further leukocyte infiltration.
These processes form a self-sustaining cycle in which lipid-induced inflammation perpetuates itself. The inability of innate and adaptive immune cells to resolve this inflammation results in plaque progression and rupture, leading to myocardial infarction or stroke.
Itaconate Suppresses Inflammation
The inflammatory behavior of immune cells is tightly linked to their metabolic state. In recent years, attention has turned to itaconate, a metabolite produced in the tricarboxylic acid (TCA) cycle by the enzyme IRG1. In activated macrophages, itaconate rapidly accumulates and restrains inflammation by inhibiting glycolysis, reducing ROS formation, type I interferon production, and IL-1β secretion.
Its anti-inflammatory effects are mediated through activation of NRF2, which regulates the expression of antioxidant proteins and suppresses NLRP3 inflammasome activation.
Studies in Irg1-deficient mice revealed enhanced immune responses and elevated secretion of pro-inflammatory cytokines IL-1β, IL-6, IL-12, and IL-18 upon lipopolysaccharide stimulation. Mutations affecting IRG1 expression also alter IL-6 and TNF-α expression and lactate production.
The synthetic derivative 4-octyl itaconate (4-OI) has already shown strong anti-inflammatory properties in mouse models, preventing lethality induced by Mycobacterium tuberculosis infection.
Researchers from the Cardiovascular Research Center at NYU Grossman School of Medicine further demonstrated that IRG1 expression increases in myeloid cells within atherosclerotic plaques but diminishes as the disease progresses. In Irg1-deficient mice, plaques were larger, less stable, and inflammation was heightened. The loss of Irg1 enhanced neutrophil extracellular trap (NET) formation, which in turn activated the NLRP3 inflammasome in macrophages, increasing IL-1β production. Thus, IRG1 deficiency amplifies pro-inflammatory cross-talk between neutrophils and macrophages.
4-OI Administration Reduces Inflammation and Promotes Plaque Remodeling
As IRG1 and itaconate levels decline during atherosclerosis progression, researchers hypothesized that itaconate replenishment could have therapeutic benefits.
In cellular experiments, 4-OI reduced cholesterol crystal-induced NET formation by approximately 50%. In macrophages pre-activated with lipopolysaccharide, 4-OI suppressed NLRP3 inflammasome activation and reduced IL-1β secretion in response to cholesterol crystals.
Administration of 4-OI to atherosclerotic mice diminished inflammation and promoted plaque remodeling and regression.
Similar effects were observed in experiments with blood cells from patients with carotid atherosclerosis. 4-OI inhibited inflammatory signaling characteristic of plasma from CVD patients while activating antioxidant and anti-inflammatory pathways in macrophages.
Conclusion
IRG1 plays a key role in suppressing pathological interactions between neutrophils and macrophages within atherosclerotic plaques. These interactions are intensified by cholesterol crystals, which activate the NLRP3 inflammasome and promote IL-1β secretion.
Expression of IRG1 and production of its metabolite, itaconate, increase in macrophages and neutrophils exposed to aggregated and oxidized LDL, the primary lipid particles accumulating in vessel walls and driving inflammation in atherosclerosis.
The IRG1–itaconate axis effectively limits inflammation in atherosclerosis and represents a promising therapeutic target for cardiovascular disease.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
The IRG1–itaconate axis protects from cholesterol-induced inflammation and atherosclerosis
