Hepatocyte-specific S100a8 and S100a9 transgene expression in mice causes Cxcl1 induction and systemic neutrophil enrichment

Here, we established a conditional mouse model with simultaneous S100a8 and S100a9 transgene expression in hepatocytes (TgS100a8a9hep) under the control of doxycycline to unravel the role of epithelial-derived Calprotectin on tissue homeostasis and inflammation. TgS100a8a9hep mice displayed a significant enrichment of neutrophils in peripheral blood and tissues with high blood content. Interestingly, Cxcl1 transcription was significantly induced in the liver of TgS100a8a9hep mice and primary hepatocytes derived thereof as compared to Control mice, accompanied by an increase of Cxcl1 serum levels. However, expression of other chemokines with a known function in neutrophil mobilization from the bone marrow, e.g. Csf3 and Cxcl2, was not altered. Doxycycline treatment of TgS100a8a9hep mice reduced Cxcl1 expression in the liver and resulted in normal numbers of neutrophils.In summary, our data demonstrate for the first time that hepatocyte-specific S100a8 and S100a9 expression induces a systemic mobilization of neutrophils by a specific activation of Cxcl1 transcription in the liver.S100 proteins are a family of small Ca2+-binding proteins [1] which share a broad spectrum of functions including regulation of enzyme activity, Ca2+-homeostasis, and interaction with components of the cytoskeleton. Belonging to this family, S100A8 and S100A9 also known as migration inhibitory factor-related protein 8 (MRP8) and 14 (MRP14) are low molecular weight proteins of 8 kDa and 14 kDa, respectively, and were initially described as proteins expressed and released by infiltrating phagocytes [2,3]. S100A8 and S100A9 form preferably heterodimers also known as Calprotectin (S100A8/A9) whereas monomers and homodimers could not be detected in isolated granulocytes and monocytes [4]. Although expression of S100A8/A9 under physiologic conditions is restricted to cells of myeloid origin including circulating neutrophils, monocytes, and eosinophils [5,6], strong induction of S100A8/A9 was detect