IgG Propels Atherosclerosis by Noncanonically Activating Macrophages

Area of Science:

• Immunology
• Cardiovascular Research
• Innate and Adaptive Immunity

Background:

• Immunoglobulin G (IgG), a key adaptive immunity component, is abundant in serum but its role in atherosclerosis is poorly understood.
• Current understanding overlooks IgG's potential contribution to cardiovascular disease pathogenesis.

Purpose of the Study:

• To investigate the pro-atherogenic role of IgG in cardiovascular disease.
• To elucidate the mechanisms by which IgG contributes to atherosclerosis development and progression.

Main Methods:

• Analysis of human coronary artery plaques and integrated single-cell plaque analyses.
• Genetic ablation of FcRn (neonatal Fc receptor) in myeloid cells of mouse models.
• Mechanistic studies involving Toll-like receptor 4 (TLR4) and NF-κB-NLRP3 inflammasome signaling.

Main Results:

• A positive correlation was found between IgG levels and cardiovascular/cerebrovascular disease severity in human plaques.
• IgG localizes to pro-inflammatory, foamy macrophages in atherosclerotic lesions, facilitated by FcRn.
• Genetic FcRn ablation in myeloid cells reduced IgG accumulation, plaque size, and inflammation in mice.
• IgG acts as an endogenous ligand for TLR4, activating NF-κB-NLRP3 inflammasome signaling and accelerating macrophage foam cell formation via LCN2.

Conclusions:

• IgG plays a significant pro-atherogenic role through a noncanonical mechanism activating innate immunity.
• Targeting IgG accumulation via FcRn presents a potential therapeutic strategy for atherosclerosis.
• This study highlights the importance of adaptive immune molecules in atherosclerosis pathogenesis via innate immune pathways.