Abstract
Our previous studies revealed a pivotal role of the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 on migratory behavior of polymorphonuclear granulocytes (PMNs) in pulmonary inflammation. Thereby, the SDF-1-CXCR4/CXCR7-axis was linked with adenosine signaling. However, the role of the SDF-1 receptors CXCR4 and CXCR7 in acute inflammatory peritonitis and peritonitis-related sepsis still remained unknown. The presented study provides new insight on the mechanism of a selective inhibition of CXCR4 (AMD3100) and CXCR7 (CCX771) in two models of peritonitis and peritonitis-related sepsis by injection of zymosan and fecal solution. We observed an increased expression of SDF-1, CXCR4, and CXCR7 in peritoneal tissue and various organs during acute inflammatory peritonitis. Selective inhibition of CXCR4 and CXCR7 reduced PMN accumulation in the peritoneal fluid and infiltration of neutrophils in lung and liver tissue in both models. Both inhibitors had no anti-inflammatory effects in A2B knockout animals (A2B–/–). AMD3100 and CCX771 treatment reduced capillary leakage and increased formation of tight junctions as a marker for microvascular permeability in wild type animals. In contrast, both inhibitors failed to improve capillary leakage in A2B–/– animals, highlighting the impact of the A2B-receptor in SDF-1 mediated signaling. After inflammation, the CXCR4 and CXCR7 antagonist induced an enhanced expression of the protective A2B adenosine receptor and an increased activation of cAMP (cyclic adenosine mono phosphate) response element-binding protein (CREB), as downstream signaling pathway of A2B. The CXCR4- and CXCR7-inhibitor reduced the release of cytokines in wild type animals via decreased intracellular phosphorylation of ERK and NFκB p65. In vitro, CXCR4 and CXCR7 antagonism diminished the chemokine release of human cells and increased cellular integrity by enhancing the expression of tight junctions. These protective effects were linked with functional A2B-receptor signaling, confirming our in vivo data. In conclusion, our study revealed new protective aspects of the pharmacological modulation of the SDF-1-CXCR4/CXCR7-axis during acute peritoneal inflammation in terms of the two hallmarks PMN migration and barrier integrity. Both anti-inflammatory effects were linked with functional adenosine A2B-receptor signaling.
Highlights
Peritonitis and peritonitis-related sepsis are still associated with a high mortality for up to 40–60% [1]
We investigated the specific role of the stromal cell-derived factor (SDF)-1 receptors CXCR4 and CXCR7 during acute inflammatory peritonitis and peritonitis-related sepsis concerning the two hallmarks of acute inflammation, migration of polymorphonuclear granulocytes (PMNs) and barrier permeability
We evaluated gene expression of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in various organs and peritoneal tissue during zymosan- and fecal-induced peritonitis
Summary
Peritonitis and peritonitis-related sepsis are still associated with a high mortality for up to 40–60% [1]. Sepsis is caused by an overshooting answer of the immune system on the infection, resulting in injuring its own organs. This acute pro-inflammatory response of the body is mainly driven by polymorphonuclear neutrophils (PMNs) as the first cells of the immune system to be recruited to the side of inflammation [7, 8]. PMNs are considered as a prognostic marker for mortality in terms of sepsis [9] as they migrate from the circulatory system into the inflamed tissue
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