The S100A12/Calprotectin-RAGE axis in ANCA- associated vasculitis (AAV) and experimental crescentic glomerulonephritis

Abstract

Rapidly progressing crescentic glomerulonephritis is a common cause of end-stage renal disease in the systemic small vessel vasculitis, anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AAV). Current treatment regimens use non-specific immunosuppressants but are often associated with severe side effects. In recent years, danger-associated molecular patterns (DAMPs) have become the focus of autoimmune research ranging from their role in pathogenesis to their potential as drug targets. The first part of this thesis investigates the circulating level of DAMPs in patients with AAV and the potential source of one DAMP, S100A12. I demonstrate that the circulating levels of 3 DAMPs calprotectin, S100A12 and HMGB1are significantly elevated in patients with AAV, IgA nephropathy (IgAN), and anti-glomerular basement membrane (GBM) disease. I then demonstrate that anti- ANCA IgG is unlikely to induce S100A12 secretion from one of the key cells involved in AAV, neutrophils. I finally demonstrate that the potential sources of S100A12 in AAV are likely to be neutrophils and monocytes in response to a serum-soluble factor that is not ANCA IgG. The second part of this thesis investigates if a calprotectin-RAGE axis is active in an experimental model of crescentic glomerulonephritis, nephrotoxic nephritis (NTN), and if RAGE antagonism has therapeutic potential. I demonstrate that a calprotectin-RAGE axis is active in NTN, with peak activity occurring at the height of the inflammatory phase of the disease. I further demonstrate that the expression of RAGE during NTN is associated with renal monocyte/macrophage infiltration. I next used the small molecule RAGE antagonist, FPS-ZM1, demonstrating that it reduces the activation of primary rat BMDMS in vitro in response to one of the calprotectin subunits, S100A9. However, in vivo, FPS-ZM1 was not protective in NTN. In summary, my data suggest that an S100A12/Calprotectin-RAGE axis is active in AAV but may not be critical to the pathogenesis of crescentic glomerulonephritis.