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Liposomes Loaded With Phosphatidylinositol 5-Phosphate Improve the Antimicrobial Response to Pseudomonas aeruginosa in Impaired Macrophages From Cystic Fibrosis Patients and Limit Airway Inflammatory Response.
- Source :
-
Frontiers in immunology [Front Immunol] 2020 Oct 02; Vol. 11, pp. 532225. Date of Electronic Publication: 2020 Oct 02 (Print Publication: 2020). - Publication Year :
- 2020
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Abstract
- Despite intensive antimicrobial and anti-inflammatory therapies, cystic fibrosis (CF) patients are subjected to chronic infections due to opportunistic pathogens, including multidrug resistant (MDR) Pseudomonas aeruginosa. Macrophages from CF patients show many evidences of reduced phagocytosis in terms of internalization capability, phagosome maturation, and intracellular bacterial killing. In this study, we investigated if apoptotic body-like liposomes (ABLs) loaded with phosphatidylinositol 5-phosphate (PI5P), known to regulate actin dynamics and vesicular trafficking, could restore phagocytic machinery while limiting inflammatory response in in vitro and in vivo models of MDR P. aeruginosa infection. Our results show that the in vitro treatment with ABL carrying PI5P (ABL/PI5P) enhances bacterial uptake, ROS production, phagosome acidification, and intracellular bacterial killing in human monocyte-derived macrophages (MDMs) with pharmacologically inhibited cystic fibrosis transmembrane conductance regulator channel (CFTR), and improve uptake and intracellular killing of MDR P. aeruginosa in CF macrophages with impaired bactericidal activity. Moreover, ABL/PI5P stimulation of CFTR-inhibited MDM infected with MDR P. aeruginosa significantly reduces NF-κB activation and the production of TNF-α, IL-1β, and IL-6, while increasing IL-10 and TGF-β levels. The therapeutic efficacy of ABL/PI5P given by pulmonary administration was evaluated in a murine model of chronic infection with MDR P. aeruginosa . The treatment with ABL/PI5P significantly reduces pulmonary neutrophil infiltrate and the levels of KC and MCP-2 cytokines in the lungs, without affecting pulmonary bacterial load. Altogether, these results show that the ABL/PI5P treatment may represent a promising host-directed therapeutic approach to improve the impaired phagocytosis and to limit the potentially tissue-damaging inflammatory response in CF.<br /> (Copyright © 2020 Poerio, De Santis, Rossi, Ranucci, De Fino, Henriquez, D’Andrea, Ciciriello, Lucidi, Nisini, Bragonzi and Fraziano.)
- Subjects :
- Cystic Fibrosis pathology
Humans
Inflammation immunology
Inflammation microbiology
Inflammation pathology
Liposomes
Macrophages, Alveolar pathology
Phosphatidylinositol Phosphates pharmacokinetics
Pseudomonas Infections pathology
Cystic Fibrosis immunology
Immunity, Innate
Macrophages, Alveolar immunology
Phosphatidylinositol Phosphates pharmacology
Pseudomonas Infections immunology
Pseudomonas aeruginosa immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 11
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 33117337
- Full Text :
- https://doi.org/10.3389/fimmu.2020.532225