A DAMP molecule of particular interest to us is S100A12. S100A12 belongs to a subgroup of S100 proteins named “Calgranulins” comprising S100A8 (calgranulin A, also referred to as myeloid-related protein, MRP8), S100A9 (calgranulin B, MRP14) and S100A12 (calgranulin C). S100A12 is specifically expressed in human neutrophilic granulocytes, accounting for approx. 5% of cytosolic protein content. As there is no expression detectable in B or T cells, this points towards a role of this protein in innate rather than adaptive immune mechanisms.
S100A12 as well as other calgranulins are well established as useful markers of both local and systemic inflammation. Their titers correlate to disease activity in rheumatic diseases, vasculitis, inflammatory bowel disease, lung disease, and infections. Even more important, phagocyte-specific S100 proteins have been found especially associated with autoinflammatory diseases, and they allow a patient stratification and prediction of relapse.
Orginially S100A12 has been reported to bind the Receptor for Advanced Glycation Endproducts (RAGE) and was thus entitled extracellular newly identified RAGE-binding protein (EN-RAGE). As we could recently demonstrate, S100A12 can bind TLR4 on human monocytes. This interaction, which can be efficiently blocked by TLR4 antagonists, triggers an up-regulation of pro-inflammatory genes in a pattern that differs from that of the primary TLR4 ligand LPS.
As both RAGE and TLR4 binding of S100A12 trigger pro-inflammatory signaling pathways our research focuses on:
- Understanding the biochemistry behind the receptor interaction
- Understanding the immunological relevance of S100A12 as trigger and promoter of pathological inflammatory responses
- Modulation of inflammatory responses by targeting S100A12