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Gamma Interferon and Interleukin-17A Differentially Influence the Response of Human Macrophages and Neutrophils to Pseudomonas aeruginosa Infection.

ABSTRACT: Macrophages are important orchestrators of inflammation during bacterial infection, acting as both effector cells and regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct inflammatory and microbicidal potentials have been described. Our previous work unveiled a positive and a negative correlation between levels of gamma interferon (IFN-?) and interleukin-17A (IL-17A), respectively, and lung function in cystic fibrosis, particularly in patients chronically infected with Pseudomonas aeruginosa This study sought to define key parameters in human antibacterial immunity under Th1- and Th17-dominated inflammatory conditions; the final aim was to identify unique characteristics that could be fine-tuned therapeutically to minimize tissue damage while maximizing bacterial clearance. Toward this aim, neutrophils were incorporated into cultures of macrophages treated with IFN-? or IL-17A and infected with P. aeruginosa The intent of this design was to model (i) initiation of inflammation by infected macrophages and (ii) delayed arrival of neutrophils and their exposure to macrophage-derived cytokines. Under these conditions, IFN-? decreased bacterial killing and promoted the production of monocyte chemoattractant protein 1 (MCP-1). In contrast, IL-17A promoted bacterial killing but did not affect MCP-1 production. The level of secretion of the pyrogen IL-1? was significantly lower in the presence of IFN-? than in the presence of IL-17A and correlated with levels of the IL1B transcript in infected macrophages. These findings support the validity of this model to investigate human antibacterial immunity. Based on these observations, the protective and damaging roles of IFN-? and IL-17A, respectively, during P. aeruginosa infection could be caused by their contrasting effects on IL-1? and MCP-1 production.

SUBMITTER: Muntaka S

PROVIDER: S-EPMC6346128 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Gamma Interferon and Interleukin-17A Differentially Influence the Response of Human Macrophages and Neutrophils to Pseudomonas aeruginosa Infection.

Muntaka Sirina S Almuhanna Yasir Y Jackson Darryl D Singh Sonali S Afryie-Asante Afrakoma A Cámara Miguel M Martínez-Pomares Luisa L

Infection and immunity 20190124 2

Macrophages are important orchestrators of inflammation during bacterial infection, acting as both effector cells and regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct inflammatory and microbicidal potentials have been described. Our previous work unveiled a positive and a negative correlation between levels of gamma interferon (IFN-γ) and interleukin-17A (IL-17A), respectively, and lung function in cystic fibrosis, particularly in pat ...[more]

PMID: 30455194

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Project description:Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-? production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-? and IL-17A playing protective and detrimental roles, respectively, in CF. In order to explore the protective effect of IFN-? in CF, the effect of IFN-? alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), on the ability of human macrophages to control P. aeruginosa growth, resist the cytotoxicity induced by this bacterium or promote inflammation was investigated. Treatment of macrophages with IFN-?, in the presence and absence of GM-CSF, failed to alter bacterial growth or macrophage survival upon P. aeruginosa infection, but changed the inflammatory potential of macrophages. IFN-? caused up-regulation of monocyte chemoattractant protein-1 (MCP-1) and TNF-? and down-regulation of IL-10 expression by infected macrophages. GM-CSF in combination with IFN-? promoted IL-6 production and further reduction of IL-10 synthesis. Comparison of TNF-? vs. IL-10 and IL-6 vs. IL-10 ratios revealed the following hierarchy in regard to the pro-inflammatory potential of human macrophages infected with P. aeruginosa: untreated < treated with GM-CSF < treated with IFN-? < treated with GM-CSF and IFN-?.

Dataset Information

Gamma Interferon and Interleukin-17A Differentially Influence the Response of Human Macrophages and Neutrophils to Pseudomonas aeruginosa Infection.

Publications

Gamma Interferon and Interleukin-17A Differentially Influence the Response of Human Macrophages and Neutrophils to Pseudomonas aeruginosa Infection.

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