Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis

Area of Science:

• Cardiovascular Science
• Immunology
• Molecular Biology

Background:

• The CANTOS trial demonstrated that blocking interleukin (IL)-1β reduces cardiovascular events in patients with prior myocardial infarction and inflammation.
• This suggests that IL-1β secretion pathways contribute to cardiovascular risk.
• The NLRP3 inflammasome, activated by cholesterol accumulation in myeloid cells, produces IL-1β and IL-18, but its role in atherosclerosis is not fully understood.

Purpose of the Study:

• To investigate the mechanisms linking NLRP3 inflammasome activation to the development of atherosclerosis.
• To explore the role of cholesterol transporters ATP binding cassette A1 and G1 (ABCA1/G1) in inflammasome activation and cardiovascular disease.

Main Methods:

• Mice with myeloid-specific Abca1/g1 deficiency were crossed with Nlrp3 or Caspase-1/11 deficient mice.
• Bone marrow from these mice was transplanted into Ldlr^-/- recipients fed a Western diet.
• Plasma IL-18 levels, splenocyte cytokine secretion, atherosclerotic lesion size, neutrophil infiltration, and neutrophil extracellular trap (NET) formation were analyzed.

Main Results:

• Myeloid Abca1/g1 deficiency led to increased plasma IL-18 and enhanced IL-1β/IL-18 secretion, indicating NLRP3 inflammasome activation.
• Nlrp3 or Caspase-1/11 deficiency reversed these effects and reduced atherosclerotic lesion size.
• Inflammasome activation promoted neutrophil accumulation and NET formation within atherosclerotic plaques, linked to systemic inflammation.
• Myeloid Abca1/g1 deficiency also activated the noncanonical inflammasome, increasing susceptibility to endotoxemia.
• Patients with Tangier disease (ABCA1 loss-of-function) exhibited elevated plasma IL-1β and IL-18 levels.

Conclusions:

• Myeloid cell cholesterol accumulation activates the NLRP3 inflammasome, promoting neutrophil recruitment and NET formation in atherosclerosis.
• These findings suggest a novel mechanism linking cholesterol metabolism, inflammasome activation, and cardiovascular disease progression.
• The observed inflammasome activation in Tangier disease patients underscores the clinical relevance of these findings.