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Arf6 regulation of glycolytic metabolism and effector functions in neutrophils

ABSTRACT: Arf6 is a small GTPase regulating many cellular processes including cytoskeletal remodeling, receptor endocytosis, and phagocytosis of pathogens. Arf6 knockdown in neutrophil (PMN)-like cells was reported to inhibit chemotactic peptide-mediated activation of phospholipase D, the oxidative burst, and 2 integrin-dependent adhesion. In mice, the migration of PMNs knock out for Arf6 to the site of inflammation was diminished and associated with reduced cell surface expression of 2 integrins. Conditional knockout mice lacking Arf6 in PMNs were used to assess the impact of Arf6 depletion on the functions and gene expression profile of PMNs isolated from the mouse air pouch injected with lipopolysaccharide (LPS). The expression of several genes was modulated in PMNs-Arf6 cKO with Lpar6 and Lacc-1 being the most up-regulated and down-regulated genes, respectively. Decreased expressed of Lacc-1 was validated at the protein level in PMN-Arf6 cKO, and silencing of Arf6 in THP-1 monocytic cells delayed LPS-mediated Lacc-1 expression. Here we report that fMLP or zymosan-induced glycolysis and oxygen consumption rate were decreased in air pouch PMNs but not in BM PMNs of Arf6 cKO mice when compared to control floxed cells. Reduced oxygen consumption correlated with decreased production of superoxide and ROS. Depletion of Arf6 in mouse PMNs also reduced phagocytosis and interfered apoptosis. The data suggest that Arf6 regulates energy metabolism, which may contribute to impaired phagocytosis, ROS production, and apoptosis in PMN-Arf6 cKO. This study provides new information on the functions and the inflammatory pathways influenced by Arf6 in PMNs.

ORGANISM(S): Mus musculus

PROVIDER: GSE151436 | GEO | 2021/05/28

REPOSITORIES: GEO

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Project description:Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications. Granulibacter bethesdensis is an emerging Gram-negative pathogen in CGD that resists killing by CGD PMN and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in normal and CGD PMN during incubation with G. bethesdensis and, simultaneously, in G. bethesdensis with normal and CGD PMN. We detected upregulation of anti-apoptotic genes (e.g., XIAP, GADD45B) and downregulation of pro-apoptotic genes (e.g., CASP8, APAF1) in infected PMN. Transcript and protein levels of inflammation and immunity-related genes were also altered. Upon interaction with PMN, G. bethesdensis altered expression of ROS-resistance genes in the presence of normal but not CGD PMN. Bacterial stress response genes, including ClpB, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knock down demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of Granulibacter growth in PMN included upregulation of pyruvate dehydrogenase. Pharmacologic inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to Granulibacter. This study expands knowledge of microbial pathogenesis by Granulibacter in cells from permissive (CGD) and non-permissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen. pathogen time series 0-1-4-24 in CGD subjects and normals : host time series 0-1-4-24 in CGD subjects and normals non-infected and infected with Gb

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Arf6 regulation of glycolytic metabolism and effector functions in neutrophils

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