单核细胞增多
造血
炎症
巨噬细胞
巨噬细胞集落刺激因子
生物
信号转导
免疫学
封锁
受体
车站3
癌症研究
细胞生物学
化学
骨髓
生物化学
干细胞
体外
作者
Wenli Liu,Mustafa Yalcınkaya,Inés Fernández Maestre,Malgorzata Olszewska,Patrick B. Ampomah,J. Brett Heimlich,Ranran Wang,Pablo Sánchez Vela,Tong Xiao,Alexander G. Bick,Ross L. Levine,Eirini P. Papapetrou,Peter Libby,Ira Tabas,Nan Wang,Alan R. Tall
标识
DOI:10.1038/s44161-023-00281-3
摘要
Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.
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