Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection

Abstract

Granulocyte colony-stimulating factor (G-CSF) regulates the production, maturation, and function of neutrophils. Its expression is often induced during infection, resulting in high concentrations of G-CSF in inflammatory exudates and in the blood, suggesting that it may regulate both local and systemic neutrophil responses. Herein, we characterize the neutrophil response in G-CSFR−/− mice following intratracheal injection with Pseudomonas aeruginosa–laden agarose beads, modeling the pulmonary infection observed in many patients with cystic fibrosis. G-CSFR−/− mice are markedly susceptible to bronchopulmonary P aeruginosa infection, exhibiting decreased survival and bacterial clearance as well as extensive damage to lung tissue. The systemic neutrophil response was mediated primarily by enhanced neutrophil release from the bone marrow rather than increased neutrophil production and was attenuated in G-CSFR−/− mice. Despite normal to increased local production of inflammatory chemokines, neutrophil accumulation into the infected lung of G-CSFR−/− mice was markedly reduced. Moreover, the percentage of apoptotic neutrophils in the lung was elevated, suggesting that G-CSF signals may play an important role in regulating neutrophil survival at the inflammatory site. Collectively, these data provide new evidence that G-CSF signals play important but specific roles in the regulation of the systemic and local neutrophil response following infection.

CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow

“…5). Consistent with previous studies (22,38), under basal conditions, 1.84% ± 0.32% of WT neutrophils were present in the blood ( Figure 1D). In contrast, the percentage of Cxcr2 -/-neutrophils in the blood was 0.57% ± 0.18% (P = 0.02).…”

Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice

“…Gregory et al 49 reported that apoptosis of neutrophils was accelerated in the Pseudomonas aeruginosa-infected lungs in G-CSFR Ϫ/Ϫ mice. Therefore, the production of G-CSF in the tumor microenvironment may promote the maintenance of tumor infiltrating neutrophils, in addition to accelerating the neutrophil production in the BM.…”

Contribution of the Prostaglandin E2/E-Prostanoid 2 Receptor Signaling Pathway in Abscess Formation in Rat Zymosan-Induced Pleurisy

“…G-CSF regulates the production and maturation of neutrophils. It also stimulates the survival of mature neutrophils (Gregory et al, 2007). These proinflammatory activities of IL-1␤, IL-6, and G-CSF may contribute to abscess formation.…”