G-CSF and GM-CSF Modify Neutrophil Functions at Concentrations found in Cystic Fibrosis

Abstract

The role of colony stimulating factors (CSFs) in cystic fibrosis (CF) circulating neutrophils has not been thoroughly evaluated, considering that the neutrophil burden of lung inflammation in these subjects is very high. The aim of this study was to assess granulocyte-CSF (G-CSF) and granulocyte-macrophage-CSF (GM-CSF) levels in CF patients in various clinical conditions and how these cytokines impact on activation and priming of neutrophils. G-CSF and GM-CSF levels were measured in sputum and serum samples of stable CF patients (n = 21) and in CF patients with acute exacerbation before and after a course of antibiotic therapy (n = 19). CSFs were tested on non CF neutrophils to investigate their effects on reactive oxygen species (ROS) production, degranulation (CD66b, elastase, lactoferrin, MMP-9), and chemotaxis. At very low concentrations found in CF patients (0.005–0.1 ng/ml), both cytokines inhibited ROS production, while higher concentrations (1–5 ng/ml) exerted a stimulatory effect. While either CSF induced elastase and MMP-9 secretion, lactoferrin levels were increased only by G-CSF. Chemotaxis was inhibited by GM-CSF, but was increased by G-CSF. However, when present together at low concentrations, CSFs increased basal and fMLP-stimulated ROS production and chemotaxis. These results suggest the CSF levels that circulating neutrophils face before extravasating into the lungs of CF patients may enhance their function contributing to the airway damage.

Hydroxychloroquine prophylaxis and treatment is ineffective in macaque and hamster SARS-CoV-2 disease models

“…We therefore also evaluated the lung concentrations of pro-inflammatory cytokines (IL-1 cytokine family, IL2, TNFa, IFNg, GM-CSF, G-CSF, etc.) and CC-chemokines involved in the recruitment of mononuclear cells (MCP-1, MIP-1a and MIP-1b) that play a role in pathogenesis and inflammatory pathology in the lung (29)(30)(31). We observed no statistically significant differences in pro-inflammatory cytokine or CC-chemokine concentrations among SARS-CoV-2 infected macaques either untreated or treated with HCQ (Figs.…”

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

“…The cleavage of another chemokine receptor, CXCR1, has also been linked to impaired bacterial clearance in CF [164]. Other pro-inflammatory signals, such as ROS [165] and colony-stimulating factors [166], are significantly raised in CF; likewise, levels of the bioactive fragment of collagen called proline-glycine-proline (PGP) which is generated by the activity of both prolylendopeptidase and matrix metalloproteinase-9 (MMP9), are also raised [167]. As PGP acts as a stimulant of neutrophil migration into tissues, as well as inducing epithelial remodelling, it has been suggested that the raised levels of PGP found in the lungs of children with CF may exacerbate the inflammatory phenotype found in these patients [167].…”

Preventing the development of severe COVID-19 by modifying immunothrombosis

“…In some respects, this can also be said of increased neutrophil apoptosis as a result of decreased levels of IL-6 and IL-8, which would otherwise increase neutrophil survival. However, decreased neutrophil survival following AZM administration also appears to be mediated by the inhibition of GM-CSF [ 155 , 156 ]. This cytokine regulates many aspects of neutrophil function and decreased levels inhibit neutrophil priming, which is important in the development of ARDS [ 155 ].…”