GM-CSF receptor/SYK/JNK/FOXO1/CD11c signaling promotes atherosclerosis

Atherosclerosis complicates chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, suggesting that a shared physiological pathway regulates inflammatory responses in these diseases wherein spleen tyrosine kinase ( SYK) is involved. We aimed to identify a shared therapeutic target for atherosclerosis and inflammatory diseases. We used Syk-knockout atherosclerosis-prone mice to determine whether SYK is involved in atherosclerosis via the inflammatory response and elucidate the mechanism of SYK signaling. The Syk-knockout mice showed reduced atherosclerosis in vivo, and macrophages derived from this strain showed ameliorated cell migration in vitro. CD11c expression decreased on Syk-knockout monocytes and macrophages; it was upregulated by forkhead box protein O1 (FOXO1) after stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF), and c-Jun amino-terminal kinase (JNK) mediated SYK signaling to FOXO1. Furthermore, FOXO1 inhibitor treatment mitigated atherosclerosis in mice. Thus, GMCSF receptor/SYK/JNK/FOXO1/CD11c signaling inmonocytes and macrophages and FOXO1 could be therapeutic targets for atherosclerosis and inflammatory diseases.

Automated summary

Atherosclerosis complicates chronic inflammatory diseases by involving a shared physiological pathway regulated by spleen tyrosine kinase (SYK). SYK is found to be involved in atherosclerosis via the inflammatory response. Knockout of SYK gene in atherosclerosis-prone mice reduces atherosclerosis in vivo and ameliorates cell migration in macrophages. CD11c expression on SYK-knockout monocytes and macrophages is regulated by forkhead box protein O1 (FOXO1) through granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, mediated by c-Jun amino-terminal kinase (JNK) signaling to FOXO1. Inhibiting FOXO1 alleviates atherosclerosis in mice, suggesting GM-CSF receptor/SYK/JNK/FOXO1/CD11c signaling and FOXO1 as potential therapeutic targets for atherosclerosis and inflammatory diseases.