Down-regulation of CXCR2 on Neutrophils in Severe Sepsis Is Mediated by Inducible Nitric Oxide Synthase–derived Nitric Oxide

Federal University of Minas Gerais, Cidade de Minas, Minas Gerais, Brazil
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 04/2007; 175(5):490-7. DOI: 10.1164/rccm.200601-103OC
Source: PubMed


The failure of neutrophils to migrate to an infection focus during severe sepsis is an important determinant of the inability of a host to deal with an infectious insult. Our laboratory has shown that inducible nitric oxide synthase (iNOS) induction and NO production contribute to the failure of neutrophils to migrate in the context of sepsis. Objectives and
We investigated whether CXCR2 expression contributed to the failure of neutrophils to migrate during severe sepsis and the role of NO in modulating CXCR2 expression on neutrophils in mice subjected to nonsevere (NS) or severe (S) cecal ligation and puncture (CLP).
Neutrophil migration to the infection focus was deficient in S-CLP mice, a phenomenon prevented by pharmacologic (aminoguanidine, l-canavanine) or genetic (iNOS gene deletion) inhibition of iNOS. The expression of CXCR2 on neutrophils from S-CLP mice was significantly reduced when compared with neutrophils from NS-CLP or sham-operated mice. CXCR2 expression was reestablished by pharmacologic and genetic inhibition of iNOS. Immunofluorescence and confocal analysis revealed that iNOS blockade reduced neutrophil CXCR2 internalization. Adhesion and emigration of neutrophils in macrophage inflammatory protein-2-stimulated mesentery microcirculation were reduced in S-CLP mice, compared with NS-CLP mice, and reestablished by pretreatment with aminoguanidine or l-canavanine. The NO donor S-nitroso-N-acetyl-d,l-penicillamine inhibited CXCL8-induced human neutrophil chemotaxis and CXCR2 expression on human and murine neutrophils.
These results highlight evidences that the failure of neutrophils to migrate to an infection focus during severe sepsis is associated with excessive NO production and NO-dependent regulation of the expression of CXCR2 on the neutrophil surface.

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Available from: Fabrício Rios-Santos
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    • "In contrast, it inhibits neutrophil migration in CLP-induced murine sepsis [120] and in NO pre-treated human neutrophils from healthy donors [121]. This defect appears to be, at least in part, dependent on the reduced expression of β 2 integrins [120], and further compounded by the NO-mediated reduction of CXCR2 surface expression on circulating neutrophils [122]. Nitric oxide reaction with reactive oxygen species (ROS) during inflammation produces peroxynitrite, which further decreases neutrophil adhesion and migration by inhibiting actin polymerization via actin S-nitrosylation [7] [123]. "
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    • "In addition, reduced surface levels of CXCR2 are observed during different pathologies such as sepsis due to receptor internalization, and results in impaired neutrophil trafficking to infection foci and reduced bactericidal effects (e.g. reduced ROS production) (Rios-Santos et al., 2007; Rose et al., 2004). Taken together, by investigating the effect of TSD on neutrophil subtypes and function , this study offers possible explanations through which sleep deprivation may increase our vulnerability to infections. "
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    • "This reduced expression may be an attempt by the host to limit excessive inflammation induced by granulocytes at the site of infection but may also be detrimental. A study from Rios-Santos et al. (40) demonstrated that mice subjected to CLP show deficient neutrophil migration to the site of infection during severe sepsis, which is associated with decreased expression of CXCR2 on the cell surface. In the present study, the expression of CXCR2 differed between survivors and nonsurvivors at follow-up. "
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