Title: Neutrophil extracellular traps (NETs) as a therapeutic target for the treatment of auto-immune inflammatory disease
Funder: Versus Arthritis

Abstract: Neutrophils are a type of white blood cell that protect us from infection. However, inappropriate activation of neutrophils, for example in auto-immune diseases such as rheumatoid arthritis (RA) and lupus (SLE), can cause them to release toxic molecules that they usually use to kill microbes directly onto the surface of our own tissues. This causes damage to small blood vessels in organs such as the kidney and the surface of our joints (cartilage). During certain types of inflammation, neutrophils can dismantle their DNA and release this outside the cell as “mesh” or “net” (called neutrophil extracellular trap, NET). NETs are covered in molecules that trap and kill bacteria, and so are an essential process that protects us from infection. However, in RA and SLE the NETs can cause the body to mis-recognise some molecules as “foreign”, and so create an inappropriate immune response (auto-antibodies) against the tissues that contain high levels of these molecules, for example in the joint and kidney. During a recent project we investigated the molecules covering RA and SLE NETs and found that some of the molecules contained chemical modifications that corresponded to many of the different types of auto-antibodies that are found in SLE and RA. We believe that NETs may be one of the causes of auto-antibody production in RA and SLE and therefore may be a new drug target for treatment of these diseases. NETs are also involved in other auto-immune diseases such as vasculitis and multiple sclerosis and so any treatment that can block NET production in RA and SLE may also be suitable for patients with other auto-immune inflammatory conditions. Auto-immune diseases affect over 4M people in the UK. RA alone affects over 0.5M adults and SLE affects around ~100,000 adults. Whilst many drugs are available to treat RA and SLE, not every patient responds in the same way or as effectively, and some patients don’t respond to therapy at all. Many approved drugs are very toxic and have nasty side effects throughout the whole body. We need new and more specific drugs that can target the specific processes and cells that cause auto-immune inflammatory diseases (e.g. NETs). In our experiments, we will isolate neutrophils from the blood of healthy individuals and patients with RA or SLE, and we will conduct a series of experiments designed to identify drugs that block NET production. We will use a validated set of over 180 new inhibitor drugs developed by pharmaceutical companies to see if they can block NET production. We will then test a short-list of the most promising inhibitor drugs to check that they have no effect on the ability of neutrophils to kill microbes. This project will identify new and more targeted therapies that can block NET production in RA and SLE, and which have the potential to treat several different auto-immune inflammatory conditions where NETs are driving the disease process and progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM