August 17th, 2017
Tumor Necrosis Factor α (TNFα) is a potent pro-inflammatory cytokine that plays a crucial role in the underlying pathogenesis of chronic inflammatory systemic diseases such as rheumatoid arthritis, obesity-induced low-grade inflammation, and inflammatory bowel disease. The success of biologics that inhibit TNFα, such as adalimumab, etanercept, and infliximab, for treatment of chronic inflammation has led to a desire for orally available small molecules that have fewer serious adverse events and are more cost efficient to produce than current TNFα antagonists.
An attractive target for anti-TNF therapy therefore is the TNFα-converting enzyme, TACE, also known as a disintegrin and metalloproteinase 17 (ADAM17), which promotes the release of soluble TNFα from its membrane-bound precursor. We have recently identified a novel regulator of TACE, a catalytically inactive member of the rhomboid family of intra-membrane proteinases called iRhom2. Mice lacking iRhom2 are unable to release TNFα from their immune cells and are therefore protected from inflammatory arthritis. The main goal of studies in our lab is to identify new therapeutic targets in chronic inflammatory disorders by using mouse models of human disease, which can provide mechanistic insights into the disease process as well as access to all disease stages.