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

¹ Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil; ² Department of Health, University of Santa Cruz, Bahia, Brazil; ³ Laboratory of Tissue Engineering and Immunopharmacology, Gonçalo Moniz Research Center/FIOCRUZ, Bahia, Brazil; and ⁴ Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil

Correspondence and requests for reprints should be addressed to Fernando Q. Cunha, Ph.D., Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, 14049–900 Ribeirão Preto, SP, Brazil. E-mail: fdqcunha{at}fmrp.usp.br

Rationale: 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 Methods: 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).

Results: 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.

Conclusion: 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.

Key Words: sepsis • neutrophil migration • CXCR2 • nitric oxide

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Nitric oxide (NO) participates in the pathogenesis of sepsis and the chemokine receptor CXCR2 has been shown to be down-regulated on neutrophils during severe sepsis. What This Study Adds to the Field Failure of migration of neutrophils to an infection focus during severe sepsis is associated with excessive NO production and NO-dependent down-regulation of CXCR2 expression on the neutrophil surface.

 

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