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

  • iScience. 2023 Jul 11;26(8):107293. doi: 10.1016/j.isci.2023.107293.
Daisuke Tsukui  1 ,  Yoshitaka Kimura  1  2 ,  Hajime Kono  1
Affiliations
  • 1. Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
  • 2. Department of Microbiology and Immunology, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
PMID: 37520709 DOI: 10.1016/j.isci.2023.107293
Abstract

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, GM-CSF receptor/Syk/JNK/FOXO1/CD11c signaling in monocytes and macrophages and FOXO1 could be therapeutic targets for atherosclerosis and inflammatory diseases.

Keywords
Immunology; Molecular biology.
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