Exosome-mediated transfer of NOD2 from platelets to monocytes: a novel therapeutic target for atherosclerosis

Atherosclerosis, the pathological basis of cardiovascular diseases including coronary artery disease and ischemic stroke, is increasingly recognized as a chronic inflammatory disease. The contribution of nucleotide-binding oligomerization domain containing 2 (NOD2), a key pattern recognition receptor in immunity, to atherosclerosis remains poorly defined. This study investigated the role of NOD2 in platelet-mediated monocyte activation and evaluated the therapeutic potential of pharmacological NOD2 inhibition. NOD2 protein wasdecreased in platelets from atherosclerotic patients and mice, accompanied by elevated NOD2 expression in peripheral blood mononuclear cells. These alterations were not attributable to transcriptional regulation. Plasma exosomes from atherosclerotic patients contained increased NOD2 protein. Accordingly, platelet activation caused a reduction in NOD2 protein within platelets and the release of NOD2-enriched exosomes that increased NOD2 expression in THP-1 monocytes. NOD2 overexpression in THP-1 cells enhanced cell migration and proinflammatory response without affecting cell adhesion and differentiation, whereas treatment with the NOD2 receptor antagonist GSK669 attenuated both processes. Mechanistically, NOD2 upregulated LOX-1 and activated the RIP2/JNK/p38 axis during THP-1 differentiation. In hyperlipidemic ApoE^-/- mice, platelet-derived exosomes carrying NOD2 exacerbated atherosclerosis, while intravenous administration of GSK669 attenuated atherosclerosis and showed efficacy comparable to aspirin in this mouse model. In conclusion, we uncover a previously unrecognized mechanism whereby platelet-to-monocyte transfer of NOD2 via exosomes drives monocyte inflammation and migration, exacerbating atherosclerosis. The anti-atherosclerotic effects of GSK669, a NOD2 receptor antagonist with previously reported antithrombotic efficacy comparable to aspirin and a favorable bleeding profile in mice, highlight NOD2 antagonism as a promising alternative therapeutic strategy against atherosclerosis.