Saswata Talukdar1,3,4, Da Young Oh1,4, Gautam Bandyopadhyay1, Dongmei Li2, Jianfeng Xu1, Joanne McNelis1, Min Lu1, Pingping Li1, Qingyun Yan2, Yimin Zhu2, Jachelle Ofrecio1, Michael Lin1, Martin B Brenner2 & Jerrold M Olefsky1
1Department of Medicine, University of California, San Diego, La Jolla, California, USA. 2Pfizer, Cardiovascular, Metabolic and Endocrine Diseases (CVMED).Diabetes Prevention and Remission, Cambridge, Massachusetts, USA. 3Present address: Pfizer, CVMED.Diabetes Prevention and Remission, Cambridge, Massachusetts, USA. 4These authors contributed equally to this work.
Correspondence to: Jerrold M Olefsky
Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes1, 2. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process3, 4, 5, 6, 7, 8. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells9, 10, 11. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models12. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet?induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.