Investigating the role of neutrophil-mediated tissue damage in a model of lupus nephritis

Systemic lupus erythematosus (SLE) is a rare autoimmune disease that affects around 5 million people worldwide. It disproportionately affects women and is incurable. SLE is a multimorbid disease, with renal damage (lupus nephritis), cardiovascular disease, arthritis and mental health issues affecting around 78% of people with SLE. Even with modern treatment it is still associated with an increased risk of shortened life expectancy. SLE is characterised by the production of multiple auto-antibodies (e.g. anti-nuclear antibodies, anti-double stranded DNA antibodies) alongside chronic, systemic inflammation. Neutrophils are innate immune cells involved in chronic inflammation and production of neutrophil extracellular traps (NETs) that expose auto-antigens (e.g. DNA, histones) leading to production of auto-antibodies. We hypothesise that neutrophil activation products including reactive oxygen species (ROS) and proteases (such as elastase and collagenase), along with auto-antibodies that bind to NETs, induce tissue damage in the kidney glomeruli of people with SLE.

Objectives

The objectives of the project are to define the role of neutrophils and neutrophil products (ROS, proteases, NETs) in tissue damage in SLE and identify therapeutic inhibitors of neutrophil activation and neutrophil-mediated tissue damage.

Novelty

Activated neutrophils are an exciting new therapeutic target to block tissue damage in auto-immune diseases. The primary supervisor has active grants which have identified small molecule kinase inhibitors to block NET production and the secondary supervisor has extensive experience in protease biology. The third supervisor who has extensive experience in developing in vitro organoid models will lead development of the in vitro organoid model of the lupus kidney.

Timeliness

SLE is a serious life-limiting disease with very few treatment options. The primary supervisor is leading a program of discovery research to identify novel therapies to target unwanted neutrophil activation in auto-immune disease. The primary supervisor has an established collaboration with a connective tissue disease consultant in Liverpool who can source neutrophils from people with SLE.

Experimental Approach

We will develop an in vitro model of SLE using co-cultures of neutrophils, neutrophil degranulation products, NET debris and serum (healthy and SLE) with endothelial (HUVEC) and epithelial (podocytes) cells in 2D and 3D organoids. We will use a range of cell-based assays to measure protease and cytokine production, cell viability, proliferation and collagen degradation. We will repeat these experiments in the presence of chemical inhibitors of NET production and neutrophil proteases (e.g. MMP inhibitors, serine protease inhibitors) in order to identify potential novel therapies for the treatment of SLE.