Molecular mechanisms underlying the S100A12-mediated activation of phagocytes: Interaction with cellular receptors and function as "damage associated molecular pattern" protein

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The granulocyte-specific protein S100A12 is overexpressed during inflammatory conditions and has been ascribed to the group of pro-inflammatory Damage Associated Molecular Pattern molecules (DAMPs). We have analyzed the characteristics of S100A12-binding to the pattern recognition receptor (PRR) RAGE (Receptor for Advanced Glycation End products). In our previously funded project we could demonstrate that S100A12 expression and release is rapidly induced in vitro and in vivo by inflammatory challenge. As other DAMPs have been shown to signal via Toll-like receptors (TLRs), we have performed surface plasmon resonance studies revealing binding of S100A12 to both RAGE and TLR4. To gain insight into the function of S100A12 we will now perform a global gene expression analysis of S100A12-induced responses of monocytes and compare this with LPS-induced gene expression profiles to get insights into the exact signalling pathways. We will elucidate the molecular mechanisms involved in the S100A12-induced activation of monocytes and the relative contribution of different PRRs. Cells will be used for in vitro-experiments after knock-down or overexpression of RAGE or the TLR4-complex, respectively. We will use RAGE-/- mice and also mice expressing a non-functional TLR4 for ex vivo and in vivo studies. In addition, a transgenic mouse over-expressing human S100A12 is planned.