It is estimated that approximately 18 million people worldwide suffer from rheumatoid arthritis (RA). Current immunosuppressive treatments have clinical efficacy, however many patients suffer severe side effects and approximately 50% of patients are refractory to therapy. This highlights the need for more diverse anti-inflammatory treatment options, which are well tolerated and have long-term efficacy in patients. One notable feature strongly associated with RA is tissue destruction and inflammation caused by oxidative stress. This is unsurprising given the persistent hypoxic conditions in the RA synovium. Numerous studies have verified that activation of the Nrf2 system (a master regulator of oxidative stress) may be therapeutically beneficial for ameliorating RA owing to its anti-inflammatory and anti-oxidative activity. This is mediated largely by protective enzymes including heme oxygenase-1 (HO-1). We previously reported that keto acids produced by the parasite, Trypansoma brucei (as well as commensal bacteria in the gut), activate Nrf2 and can directly suppress inflammatory responses and dysregulated metabolism in human immune cells, via HO-1 activation. Most recently, we have generated novel data demonstrating that these compounds can promote stem cell differentiation and induce the expression of genes associated with bone/cartilage formation. The purpose of this study is to determine if these compounds have potential for use in the treatment of RA, given the strong connection between oxidative stress and tissue damage in this disease. Of note, indole based products have recently been highlighted as promising therapeutics for inflammatory bowel disease and parasite derived products have long been explored as anti-inflammatories to treat a range of autoimmune and inflammatory diseases. Validation of these molecules in RA patient samples and in stem cells will support future studies that could potentially lead to the development of new RA therapies.
