The immunometabolite Itaconate as a novel driver of TLR7-mediated Systemic Lupus Erythematosus (SLE) 

Systemic lupus erythematosus (SLE; lupus) is a chronic, debilitating disease that can occur when the body starts attacking itself. Lupus can affect everyone, although it largely affects women, and disease onset can occur as early as childhood. Whilst many different therapies and management strategies for lupus exist, lupus remains a lifelong disease characterized by elevated inflammatory proteins and antibodies that attack our own immune system (autoantibodies), with a concurrent gradual decrease in quality of life. Although extensive research has elucidated how lupus develops and is sustained, the underlying mechanisms remain elusive.

A growing area of interest is how metabolism (how our bodies produce energy) can be rewired during chronic autoimmune conditions such as lupus, resulting in disease onset or greater disease severity. It is emerging that specific metabolites produced by white blood cells in our immune system can increase the production of certain inflammatory proteins in different contexts. How these metabolites may be detrimental in lupus, however, is unknown and remains an open question. Answering this question forms the basis of Dr Ryan’s Lupus Research Alliance and Rheumatology Research Foundation Empowering Lupus Research Partnership Scientist Development Award proposal.

In his preliminary data, Dr Ryan has re-analyzed existing human lupus datasets to identify a key ‘break’ in the metabolism of lupus patients compared with healthy controls. Lupus patients exhibit disrupted energy production, and the white blood cells of lupus patients have significantly altered levels of the metabolite itaconate. This is especially intriguing as itaconate is known to be a key regulator of inflammation. Using human lupus patient samples as well as standard mouse models that mimic lupus, Dr Ryan will explore how changes in itaconate levels contributes to lupus disease.

Dr Ryan’s Scientist Development Award proposal will characterize 1) how changes in itaconate levels alters the activity of immune cells driving lupus disease, and 2) the mechanisms underlying increased inflammation and autoantibodies in humans and mice as a consequence of altered itaconate levels in lupus. The ultimate goal of Dr Ryan’s project is to help patients by developing new treatments for lupus targeting this new inflammatory pathway.

What this means for people with lupus: 

Dr Ryan’s discoveries will provide a detailed, mechanistic understanding for how dysregulated immunometabolism – and metabolites – drives lupus pathophysiology.  This study will identify new targets for the treatment of lupus and could lead to the development of new therapies to protect against lupus and improve the quality of life for lupus patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by excess interferon (IFN) and autoantibody production that affects 5 million people globally. There is an urgent need to better understand disease triggers and pathogenesis to define new therapeutic targets. Immunometabolic rewiring characterizes SLE but how metabolites drive SLE remains mostly unknown and underexplored. The objective of this Lupus Research Alliance and Rheumatology Research Foundation Empowering Lupus Research Partnership Scientist Development Award project is to identify dysregulated metabolites that drive and sustain SLE pathogenesis.

By analyzing human SLE data and using SLE mouse models, Dr Ryan has identified alterations in levels of the metabolite itaconate associated with SLE. In this project, two independent aims will be pursued investigating how changes in itaconate levels affect development of SLE. First, Dr Ryan will perform single-cell and bulk transcriptomics and metabolomics of human pediatric SLE samples. In parallel, two independent lupus mouse models will be used to bridge the bench-to-bedside gap in SLE. This will identify novel mechanisms and decipher the immune cells involved in changes in itaconate levels associated with SLE. Second, Dr Ryan will investigate the mechanistic basis of how alterations in itaconate levels contributes to excess IFN and autoantibody production in SLE, with particular attention given to TLR7 – an important driver of human SLE – in this process. Studying itaconate-TLR7 crosstalk in SLE will elucidate new biology underlying this pathophysiological signalling pathway and identify potential new biomarkers and therapeutic targets for SLE.

The goal of this project is to characterize a mechanistic basis for dysregulated immunometabolism as a critical driver of excess IFN and autoantibody production in SLE. Successful completion of this Scientist Development Award will initiate transformative discoveries in autoimmune disease, driving the development of safer and more effective treatments for people living with SLE.