Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils

Abstract

Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model.

Neutrophils Affect IL-33 Processing in Response to the Respiratory Allergen Alternaria alternata

“…The BALF of C57BL/6 mice mostly contained eosinophils (Figure 1C), while BALB/c mice responded with a neutrophilia (Figure 1D). As expected, the neutrophilic inflammation in BALB/c was accompanied by an upregulation of G-CSF (Figure 1E) in the lungs 12 hours after the Alt treatment, consistent with the function of G-CSF in promoting the recruitment of neutrophils from the bone marrow after airway allergen challenge (27,28). Remarkably, both mouse strains showed a fast upregulation of IL-5 in the lungs after the Alt treatment (Figure 1F).…”

Granulocyte-colony stimulating factor: Missing link for stratification of type 2–high and type 2–low chronic rhinosinusitis patients

“…It was described that also other cell types such as epithelial cells, endothelial cells, fibroblasts, smooth muscle cells and macrophages can produce G-CSF. [19][20][21][22] Remarkably, the type 2-high patient with the highest elastase level (indicated in red on figure 4C), suggesting a mixed eosinophilic and neutrophilic inflammation, showed a high rate of double positive cells (90.5%), more similar to the levels of type 2-low patients.…”

“…Current treatment methods for chronic rhinosinusitis, such as glucocorticosteroids, lead to increased G-CSF levels and blocking G-CSF could thus be beneficial. 19,46 Depletion of G-CSF leads to diminished neutrophil numbers, however, several studies showed that granulopoiesis can still take place during infection and in steady state, independently of G-CSF. 47 Another possibility is targeting the receptor for G-CSF, as G-CSFR is only expressed on a limited number of cells.…”

Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma

“…After the observation that F.p. induced G-CSF and airway neutrophilia in BAL samples, a phenomenon previously observed with dexamethasone and lipopolysaccharide ( 69 ), we tested whether steroid-driven G-CSF was an important downstream mechanism contributing to airway neutrophilia by blocking G-CSF with anti–G-CSF–neutralizing mAbs (aG-CSF; Fig. 5A).…”