Membrane-bound Interleukin-1α mediates leukocyte adhesion during atherogenesis

Area of Science:

• Cardiovascular Biology
• Immunology
• Inflammation Research

Background:

• The interleukin-1 (IL-1) family and NLRP3 inflammasome are implicated in atherosclerosis.
• Mechanisms linking IL-1α, IL-1β, and NLRP3 to atherosclerosis require further elucidation.
• IL-1α exerts pro-inflammatory effects independent of the NLRP3 inflammasome.

Purpose of the Study:

• To investigate the distinct roles of IL-1α, IL-1β, and NLRP3 in atherosclerosis pathogenesis.
• To characterize the mechanisms by which IL-1α contributes to atherosclerosis development.

Main Methods:

• A non-genetic model using PCSK9-AAV8 mutant viruses and a high-fat diet was employed in wildtype and knockout mice (Il1a^-/-, Nlrp3^-/-, Il1b^-/-).
• Atherosclerotic plaque area, lipid accumulation, and serum cytokine levels were analyzed.
• Cellular mechanisms involving IL-1α translocation, myristoylation, and protein-protein interactions were examined in myeloid cells and endothelial cells.

Main Results:

• PCSK9-Il1a^-/- mice exhibited significantly reduced atherosclerotic plaque area and lipid accumulation compared to controls.
• No significant differences in atherosclerosis were observed in PCSK9-Nlrp3^-/- or PCSK9-Il1b^-/- mice.
• IL-1α translocation to the cell surface (csIL-1α) in myeloid cells, regulated by myristoylation, was observed and correlated with hypercholesterolemia.
• csIL-1α interaction with IL1R1 on endothelial cells promoted VCAM1 expression and monocyte adhesion, which was blocked by neutralizing antibodies.

Conclusions:

• IL-1α on the surface of circulating leukocytes is crucial for atherosclerosis development.
• Protection from atherosclerosis in Il1a^-/- mice was independent of circulating cytokines and NLRP3 inflammasome activity.
• Myristoylation-dependent IL-1α cell surface translocation in myeloid cells contributes to leukocyte adhesion and atherosclerosis progression.