Activation of iRhom2/ADAM17/HB-EGF/EGFR pathway in immune complex nephritis

Immune complex deposition leads to recruitment and activation of cells in the kidney via Fcgamma receptors (FCgammaR) and C5a receptors (C5aR) and production of inflammatory mediators, including proteases, growth factors such as heparin-binding epidermal growth factor-like growth factor (HB-EGF), and cytokines such as TNFalpha. Our preliminary data reveal that C5a and immune complexes activate the cell surface metalloproteinase ADAM 17 (a disintegrin and metalloproteinase 17). HB-EGF has recently emerged as a crucial mediator of glomerulonephritis (GN), and ADAM17, the principal sheddase of HB-EGF, is critical for its functional activation and binding to its receptor, the epidermal growth factor receptor. Importantly, iRhomboid2 (iRhom2), the newly discovered essential co-factor and regulator of ADAM17, is required for the ADAMI 7-dependent release of HB-EGF. The mechanism by which HB-EGF shedding is trigged by immune complexes, the role of activation of HB-EGF by ADAM17 and iRhom2 in and the source of HB-EGF are unexplored potential therapeutic targets. We will use in vitro experiments and animal models of GN to define the role of the cell surface metalloproteinase ADAM17 in immune complex-mediated kidney injury and to determine whether blockade of ADAM 17 or iRhom2 could be a new target to treat GN.