Proinflammatory S100A12 can activate human monocytes via toll-like receptor 4

Foell D., Wittkowski H., Kessel C., Lüken A., Weinhage T., Varga G., Vogl T., Wirth T., Viemann D., Björk P., Van Zoelen M., Gohar F., Srikrishna G., Kraft M., Roth J.

Zusammenfassung

Rationale: S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to thegroupofdamage- associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far. Objectives: We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. Methods: CirculatingS100A12wasdeterminedin patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation byactivation ofhumanmonocytesafter specific receptor interaction was investigated by a series of in vitro experiments. Measurements and Main Results: S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 onmonocytes or TLR4 expressing cell lines (HEK-TCM) abrogatestherespective inflammatorysignal. Onthecontrary,blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling inmonocytes and RAGE-expressing HEK293 cells. Conclusions:Human S100A12 is an endogenousTLR4 ligand that inducesmonocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis. Copyright © 2013 by the American Thoracic Society.