S100A12 as danger signal

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:

  1. Understanding the biochemistry behind the receptor interaction
  2. Understanding the immunological relevance of S100A12 as trigger and promoter of pathological inflammatory responses
  3. Modulation of inflammatory responses by targeting S100A12

Figure: S100A12 can perpetuate inflammatory mechanisms. 1) A initial pro-inflammatory stimulus, e.g. lipopolysaccharide (LPS) triggers - among others - the NFkB driven expression 2) of calgranulins via TLR4 expressed on granulocytes. 3) Proteins are released from cells via a tubulin-dependent alternative secretory pathway. 4) Once extracellular, S100A12 can bind TLR4 or RAGE on target cells. 5) In monocytes or granulocytes NFkB-dependent expression of pro-inflammatory cytokines like IL-1b, IL-6, IL-18 or TNFa are triggered. 6) IL-1b in particular can in turn stimulate its own secretion by autocrine feedback-loops or trigger additional IL-1b release from other cells. 7) Finally, Calgranulins can activate endothelial cells via TLR4- and RAGE-dependent pathways. This results in NFkB-driven expression of adhesion markers like intracellular and vascular adhesion molecules (ICAMs, VCAMs) or selectins on the microvascular endothelium. 8) In addition, monocytes and granulocytes are attracted along a chemokine (e.g. IL-8, MCP-1) gradient to the site of inflammation. Crossing the endothelium is facilitated by calgranulin-triggered upregulation of Mac-1 (CD11b-CD18) and its subsequent binding to ICAM-1. Thus, calgranulins in concert with IL1-1b are orchestrating a vicious autoinflammatory circle that is believed to be a key pathological mechanism in autoinflammatory diseases. (Adapted from C. Kessel et al., Clin Immunol, 2012 )


Research Group "Alarmins and Innate Immunity"


Research Group Leader:
Christoph Kessel, PhD

Group Members:
Emely Verwegen, MSc (PhD candidate)

Giulia Armaroli, MD (med doctoral student)

Niklas Gruen (med doctoral student)

Jana Zell (master student)
Sabrina Fühner, BTA
Melanie Saers, MTA