Novel reprogramming of neutrophils modulates inflammation resolution during atherosclerosis

• Published in: Science advances Vol. 5; no. 2; p. eaav2309
• Main Authors: Geng, Shuo, Zhang, Yao, Lee, Christina, Li, Liwu
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.02.2019
• Subjects: Animals; Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cellular Reprogramming; Disease Models, Animal; Disease Susceptibility; Endotoxemia - complications; Immunology; Inflammation - complications; Inflammation - immunology; Inflammation - metabolism; Life Sciences; Male; Mice; Mice, Knockout; Neutrophils - immunology; Neutrophils - metabolism; Neutrophils - pathology; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Reactive Oxygen Species - metabolism; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aav2309

Nonresolving inflammation perpetuated by innate leukocytes is involved in the pathogenesis of unstable atherosclerosis. However, the role and regulation of neutrophils related to nonresolving inflammation and atherosclerosis are poorly understood. We report herein that chronic subclinical endotoxemia, a risk factor for atherosclerosis, skewed neutrophils into a nonresolving inflammatory state with elevated levels of inflammatory mediators (Dectin-1, MMP9, and LTB4) and reduced levels of homeostatic mediators (LRRC32, TGFβ, and FPN). The polarization of neutrophils was due to ROS-mediated activation of oxCAMKII, caused by altered peroxisome homeostasis and reduced lysosome fusion. Application of 4-phenylbutyrate (4-PBA) enhanced peroxisome homeostasis of neutrophils, reduced oxCAMKII, and rebalanced the expression profiles of pro- and anti-inflammatory mediators. Adoptive transfer of neutrophils programmed by subclinical endotoxemia rendered exacerbated atherosclerosis. In contrast, transfer of ex vivo programmed neutrophils by 4-PBA reduced the pathogenesis of atherosclerosis. Our data define novel neutrophil dynamics associated with the progression and regression of atherosclerosis.