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Limited proteolysis of neutrophil granule proteins by the bacterial protease RgpB 2 depletes neutrophil antimicrobial capacity

ABSTRACT: Neutrophils are highly abundant in the gingival tissues where they play an essential role in immune homeostasis by preventing microbial invasion. Here, we show that the oral periodontal pathogen Porphyromonas gingivalis utilizes its cysteine proteases (gingipains) to disengage phagosomal antimicrobial capacity without inducing neutrophil apoptosis. Arginine gingipains are a sub-family of trypsin-like proteases produced by P. gingivalis that cleave several host proteins at arginine residues. We found that RgpB action is not limited to the extracellular or plasma membrane-associated host proteins but can proteolytically modify several intracellular proteins in neutrophils. We used 2D-DIGE coupled with mass spectrometry to identify neutrophil proteins susceptible to RgpB-mediated cleavage and determined the impact of these modifications on neutrophil antimicrobial capacity and inflammatory responses. RgpB cleaved several cytoskeletal and cytoplasmic proteins, including metabolic enzymes and antimicrobial proteins such as neutrophil elastase, myeloperoxidase, and proteinase 3 within neutrophil granules. RgpB also directly primed neutrophils, increasing integrin expression and inducing broad transcriptional changes, consistent with proinflammatory reprogramming. However, despite their primed status and augmented inflammatory capacity, RgpB-treated neutrophils were conducive to intracellular bacterial survival due to the reduced activity of granule proteins and oxidative burst. Thus, our data show a previously unknown role for P. gingivalis proteases in the systematic inactivation of neutrophil microbicidal capacity via proteolysis of intracellular proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279027 | GEO | 2024/10/08

REPOSITORIES: GEO

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Project description:Abstract BACKGROUND: Gene expression profiling (GEP) in cells obtained from peripheral blood has demonstrated to be a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature availble on gene expression markers associated to Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated to critical respiratory illness in this disease is not known to the present moment. RESULTS: By using Agilent microarray chips, we have profiled gene expression signatures in whole blood of 28 COPD patients hospitalized with distinct degree of respiratory compromise.12 of them needed of admission to the ICU, while 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparison of transcript levels between ICU and non ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to select, annotate and visualize genes by function and pathway (gene ontology). T-test evidenced 1501 genes differentially expressed between ICU and non ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients showed increased levels of neutrohil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This ?neutrophil signature? was paralleled by necessity of advanced respiratory and vital support, and presence of bacterial infection. CONCLUSION: study of transcriptomic signatures in blood suggests a central role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement / modulation of the expression of these genes could represent an option for clinical monitoring and treatment of severe COPD exacerbations. Keywords: COPD, critical, expression, gene, microarray, neutrophil, proteases.

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Limited proteolysis of neutrophil granule proteins by the bacterial protease RgpB 2 depletes neutrophil antimicrobial capacity

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