Related Experiment Videos
Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis
C J Cummings1, T R Martin, C W Frevert
1Medical Research Service, Seattle Veterans Affairs Medical Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine 98195, USA.
Abstract:
Neutrophils (polymorphonuclear neutrophils; PMN) and a redundant system of chemotactic cytokines (chemokines) have been implicated in the pathogenesis of the acute respiratory distress syndrome in patients with sepsis. PMN express two cell surface receptors for the CXC chemokines, CXCR1 and CXCR2. We investigated the expression and function of these receptors in patients with severe sepsis. Compared with normal donors, CXCR2 surface expression was down-regulated by 50% on PMN from septic patients (p < 0.005), while CXCR1 expression persisted. In vitro migratory responses to the CXCR1 ligand, IL-8, were similar in PMN from septic patients and normal donors. By contrast, the migratory response to the CXCR2 ligands, epithelial cell-derived neutrophil activator (ENA-78) and the growth-related oncogene proteins, was markedly suppressed in PMN from septic patients (p < 0.05). Ab specific for CXCR1 blocked in vitro migration of PMN from septic patients to IL-8 (p < 0.05), but not to FMLP. Thus, functionally significant down-regulation of CXCR2 occurs on PMN in septic patients. We conclude that in a complex milieu of multiple CXC chemokines, CXCR1 functions as the single dominant CXC chemokine receptor in patients with sepsis. These observations offer a potential strategy for attenuating adverse inflammation in sepsis while preserving host defenses mediated by bacteria-derived peptides such as FMLP.
Insights
In sepsis patients, neutrophils show reduced CXCR2 receptors, impairing migration to certain chemokines. CXCR1 remains dominant, suggesting a therapeutic target for inflammation while preserving host defense.
Area of Science:
- Immunology
- Critical Care Medicine
- Molecular Biology
Background:
- Neutrophils (polymorphonuclear neutrophils; PMN) and chemokines are key in sepsis-induced acute respiratory distress syndrome (ARDS).
- PMN utilize CXCR1 and CXCR2 receptors for CXC chemokines, influencing inflammatory responses.
Purpose of the Study:
- To investigate the expression and function of CXCR1 and CXCR2 receptors on PMN in severe sepsis patients.
- To understand the role of these receptors in sepsis pathogenesis and identify potential therapeutic targets.
Main Methods:
- Flow cytometry to assess CXCR2 surface expression on PMN from septic patients and normal donors.
- In vitro migration assays using specific chemokine ligands (IL-8, ENA-78, GRO) and blocking antibodies.
Main Results:
- CXCR2 surface expression was significantly down-regulated (50%) on PMN from septic patients compared to controls.
- PMN from septic patients showed suppressed migratory responses to CXCR2 ligands (ENA-78, GRO) but not to the CXCR1 ligand (IL-8).
- Antibody blockade of CXCR1 inhibited IL-8-induced migration, confirming CXCR1's role.
Conclusions:
- A functional downregulation of CXCR2 occurs on PMN in sepsis, impacting chemokine-mediated migration.
- CXCR1 emerges as the dominant CXC chemokine receptor in sepsis, potentially allowing targeted anti-inflammatory strategies without compromising essential host defenses against pathogens.