IgG Propels Atherosclerosis by Noncanonically Activating Macrophages

Despite being a central component of adaptive immunity and a highly abundant serum protein, the contribution of IgG to the milieu of atherosclerosis remains unappreciated. Here, we identify a pro-atherogenic role for IgG as it activates an innate immune cascade, independent of its classical antigen-neutralizing function. Analyses of human coronary artery plaques reveal a positive correlation between IgG and cardiovascular and cerebrovascular disease severity. Integrated single-cell plaque analyses localize IgG, coinciding with its recycling receptor FcRn, to pro-inflammatory and foamy macrophages. Genetic ablation of FcRn in myeloid cells prevents IgG from accumulating in mouse atherosclerotic lesions, diminishing plaque size and inflammation. Mechanistically, IgG acts as an endogenous ligand for TLR4, triggering NF-κB-NLRP3 inflammasome signaling without requiring its antigen-binding domain. Additionally, IgG accelerates macrophage foam cell formation through upregulation of downstream effector LCN2. Our work uncovers a role for previously overlooked adaptive immune molecules in the pathogenesis of atherosclerosis through a noncanonical mechanism linked with innate immunity.