Macrophage junctional adhesion molecule-like (JAML) protein promotes NLRP3 inflammasome activation in the development of atherosclerosis.

Inflammation plays a crucial role in the progression of atherosclerosis. Junctional adhesion molecule-like protein (JAML), a type-I transmembrane glycoprotein, activates downstream signaling pathways. However, the precise role of macrophage-derived JAML in inflammation and atherosclerosis remains unclear. This study aimed to generate mice with macrophage-specific deletion or overexpression of JAML, with the focus of assessing its impact on macrophage function and elucidating its regulatory mechanism in atherosclerosis. High-throughput data screening was employed to investigate JAML expression in atherosclerosis, and macrophage-specific JAML-knockout and transgenic mice models were utilized to examine the effects of JAML on atherosclerosis. Furthermore, the role of JAML was assessed using Oil Red O staining, RNA-sequencing analysis, and co-immunoprecipitation techniques. Increased JAML expression was observed in macrophages from both mice and patients with atherosclerosis. Macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, whereas macrophage-specific JAML overexpression exacerbated these conditions. Mechanistically, JAML deletion inhibited inflammation by decreasing nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, which consequently suppressed the nuclear factor kappa B (NF-κB) pathway and NLRP3 inflammasome activation. Taken together, these findings demonstrate that macrophage-expressed JAML facilitates the progression of atherosclerosis by activating the NF-κB pathway and NLRP3 inflammasome through nuclear migration and phosphorylation of PKM2. Notably, our study revealed a novel mechanism for the regulation of NLRP3 inflammasome activation in atherosclerosis. Therefore, targeting JAML may be an effective treatment strategy for atherosclerosis, a condition characterized by chronic inflammation.