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

Abstract

BackgroundCalprotectin consists of the Ca2+-binding proteins S100a8 and S100a9 that are induced in epithelial cells in response to tissue damage and infection. Both proteins are also secreted by activated innate immune cells and numerous studies demonstrate their crucial role in pathological conditions of acute and chronic inflammation.ResultsHere, 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.ConclusionIn 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.

S100A8/A9 and S100A9 reduce acute lung injury

“…In contrast to S100A8, which inhibits MC activation, 11 S100A9 provoked activation 1–4 h post inhalation (Figure 2e) and cytokines and chemokines released from preformed stores 4 may contribute to the leucocyte infiltration seen over 4–6 h. The rapid induction of CXCL‐1 and CXCL‐2 mRNA 1 h post‐inhalation of S100A9 may contribute; responses to S100A8/A9 were weaker and transient. CXCL‐1 and CXCL‐2 are neutrophil chemoattractants and simultaneous transgenic overexpression of S100A8 and S100A9 in murine hepatocytes promoted neutrophil mobilisation via CXCL‐1 induction 34 . Our results corroborate its likely contribution seen with exogenous S100A9 and S100A8/A9 (Figure 1b).…”

NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

“…However, calprotectin regulates the hepatic expression of both CXCL1 and CXCL2. s100a9 −/− mice express reduced levels of both chemokines upon liver injury 7 and transgenic expression of S100A8 and S100A9 stimulates overproduction of CXCL1 and mobilization of neutrophils from the bone marrow 24 . Furthermore, neutrophil recruitment is reduced in s100a9 −/− mice in acute DEN injury ( Supplementary Fig.…”

Erythropoietin enhances Kupffer cell number and activity in the challenged liver

“…However, the observation that EPO also increased the levels of CXCL1 transcripts in the liver of LysM cre -Epor fl/fl mice, suggests that EPO-responsive cells other than KCs may produce CXCL1. Hepatocytes have been shown to express a functional EPO-R 66 , 75 and these cells may be candidates to mobilize neutrophils from the BM via their release of CXCL1 83 . In conclusion, we report a novel function of EPO associated with the regulation of KC number and function in the liver.…”