The Role of TLR4-ligands S100A8/A9 and S100A12 in Familial Mediterranean Fever (FMF)

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Familial Mediterranean Fever (FMF) is an autoinflammatory syndrome associated with the activation of phagocytic cells and an oversecretion of the proinflammatory cytokine interleukin-1 beta. The discovery of pyrin mutations as the genetic basis of this autoinflammatory disorder opened up new avenues of research linking dysfunction of intracellular processes, e.g. alternative secretory pathways, and immune dysregulation involving inflammasome-dependent recruitment and processing of IL-1beta. However, the exact pathogenic mechanisms in FMF are still elusive. We have demonstrated that the phagocyte-derived Damage Associated Molecular Pattern (DAMP) proteins S100A8 and S100A9 as well as S100A12 are found at excessive concentrations in serum from FMF patients. These proteins are, as IL-1beta, released by alternative secretory pathways and exhibit pro-inflammatory effects through interaction with Pattern Recognition Receptors (PRRs). More specifically, S100A8 and S100A9 as well as S100A12 have been recently described as Toll-like receptor 4 (TLR-4) activators. The potential function of pyrin involved in phagocyte-specific S100-protein secretion, its relation to IL-1, and the reason for excessively high concentrations of these proteins in FMF have not been characterized to date. We hypothesize that mutated pyrin drives FMF pathophysiology via interaction with the cytoskeleton and alteration of secretory pathways, leading to high amounts of specific pro-inflammatory molecules like the phagocyte-specific S100-proteins. In order to investigate the role of S100-proteins in FMF, we propose to analyze their expression, secretion and pro-inflammatory functions in pyrin mutated mice (FMF mice) and in cell-lines transfected with constructs carrying the FMF pyrin mutation. Additionally, to examine the impact of S100-proteins on the pathogenesis of FMF in vivo, we plan to cross S100A9 deficient mice (S100A9-/- mice) and transgenic S100A12 overexpressing mice (S100A12-tg mice) with FMF mice to define the inflammatory phenotype of these animals.