The role of CC-chemokine receptor 4 in murine polymicrobial sepsis
© BioMed Central Ltd 2007
Published: 26 September 2007
Chemokines and chemokine receptors are crucially involved in the mechanisms leading to septic shock after severe systemic infections. The CC-chemokine receptor 4 (CCR4) is predominantly expressed on T cells driving the immune response in a Th2 direction. Interestingly, CCR4 knockout (KO) mice show no phenotype in allergy models. In contrast, they are highly protected in the lipopolysaccharide shock model. We analyzed the role of CCR4 in a murine model or polymicrobial sepsis, colon ascendens stent peritonitis (CASP).
Materials and methods
In the CASP model, a stent is surgically inserted into the ascending colon of experimental mice. This leads to a persistent leakage of the gut with defined size and – depending on the stent size – to a lethal or sublethal polymicrobial sepsis. We performed 16 G CASP operations in CCR4 KO mice or wild-type (WT) controls. For ex vivo analysis, organ expression of CCR4 and its ligands, CCL17 and CCL21 were detected by real-time PCR. The bacterial loads of various organs were analyzed. Additionally, tissue cytokine levels were detected by cytometric bead array. Finally, adoptive transfer experiments from CCR4 KO mice to WT animals with or without CASP-induced peritonitis were performed.
Similarly to the lipopolysaccharide shock, CCR4 KO mice are protected in the CASP model. After sepsis induction, CR4 is massively downregulated, whereas expression of the ligands seems to be not severely affected. The absence of CCR4 signals improves bacterial clearance in the investigated organs. In organs of septic CCR4 KO mice significantly reduced IL-6 and monocyte chemoattractant protein-1 levels were found as compared with the WT controls. Astonishingly, adoptive transfer of CCR4 KO splenocytes from CASP mice in WT animals resulted in a strongly reduced susceptibility of these mice to the CASP procedure, whereas transfer of WT splenocytes did not affect the outcome.
We report a significant role of CCR4 signals in a clinically relevant polymicrobial sepsis model.