Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis
More than two decades after cloning the cystic fibrosis transmembrane regulator (CFTR) gene, the defective gene in cystic fibrosis (CF), we still do not understand how dysfunction of this ion channel causes lung disease and the tremendous neutrophil burden which persists within the airways; nor why...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fcimb.2017.00243/full |
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| author | Benoît S. Marteyn Benoît S. Marteyn Benoît S. Marteyn Pierre-Régis Burgel Pierre-Régis Burgel Laurent Meijer Véronique Witko-Sarsat Véronique Witko-Sarsat Véronique Witko-Sarsat |
| author_facet | Benoît S. Marteyn Benoît S. Marteyn Benoît S. Marteyn Pierre-Régis Burgel Pierre-Régis Burgel Laurent Meijer Véronique Witko-Sarsat Véronique Witko-Sarsat Véronique Witko-Sarsat |
| author_sort | Benoît S. Marteyn |
| collection | DOAJ |
| description | More than two decades after cloning the cystic fibrosis transmembrane regulator (CFTR) gene, the defective gene in cystic fibrosis (CF), we still do not understand how dysfunction of this ion channel causes lung disease and the tremendous neutrophil burden which persists within the airways; nor why chronic colonization by Pseudomonas aeruginosa develops in CF patients who are thought to be immunocompetent. It appears that the microenvironment within the lung of CF patients provides favorable conditions for both P. aeruginosa colonization and neutrophil survival. In this context, the ability of bacteria to induce hypoxia, which in turn affects neutrophil survival is an additional level of complexity that needs to be accounted for when controlling neutrophil fate in CF. Recent studies have underscored the importance of neutrophils in innate immunity and their functions appear to extend far beyond their well-described role in antibacterial defense. Perhaps a disturbance in neutrophil reprogramming during the course of an infection severely modulates the inflammatory response in CF. Furthermore there is an emerging concept that the CFTR itself may be an immune modulator and stimulating CFTR function in CF patients could promote neutrophil and macrophages antimicrobial function. Fostering the resolution of inflammation by favoring neutrophil apoptosis could preserve their microbicidal activities but decrease their proinflammatory potential. In this context, triggering neutrophil apoptosis with roscovitine may be a potential therapeutic option and this is currently being evaluated in CF patients. In the present review we discuss how neutrophils functions are disturbed in CF and how this may relate to chronic infection with P. aeuginosa and we propose novel research directions aimed at modulating neutrophil survival, dampening lung inflammation and ultimately leading to an amelioration of the lung disease. |
| first_indexed | 2024-04-12T02:13:08Z |
| format | Article |
| id | doaj.art-18c4640a463b44d2a5dc388099bcac6c |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-04-12T02:13:08Z |
| publishDate | 2017-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-18c4640a463b44d2a5dc388099bcac6c2022-12-22T03:52:19ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882017-06-01710.3389/fcimb.2017.00243270609Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic FibrosisBenoît S. Marteyn0Benoît S. Marteyn1Benoît S. Marteyn2Pierre-Régis Burgel3Pierre-Régis Burgel4Laurent Meijer5Véronique Witko-Sarsat6Véronique Witko-Sarsat7Véronique Witko-Sarsat8Unité de Pathogénie Microbienne Moléculaire, Institut PasteurParis, FranceInstitut National de la Santé et de la Recherche Médicale, U12021202Paris, FranceInstitut Gustave RoussyVillejuif, FranceUniversité Paris Descartes, Sorbonne Paris CitéParis, FrancePneumology Department, Hôpital CochinParis, FranceManRos Therapeutics, Centre de PerharidyRoscoff, FranceInstitut National de la Santé et de la Recherche Médicale, U1016, Institut CochinParis, FranceCentre National de la Recherche Scientifique-UMR 8104Paris, FranceCenter of Excellence, Labex InflamexParis, FranceMore than two decades after cloning the cystic fibrosis transmembrane regulator (CFTR) gene, the defective gene in cystic fibrosis (CF), we still do not understand how dysfunction of this ion channel causes lung disease and the tremendous neutrophil burden which persists within the airways; nor why chronic colonization by Pseudomonas aeruginosa develops in CF patients who are thought to be immunocompetent. It appears that the microenvironment within the lung of CF patients provides favorable conditions for both P. aeruginosa colonization and neutrophil survival. In this context, the ability of bacteria to induce hypoxia, which in turn affects neutrophil survival is an additional level of complexity that needs to be accounted for when controlling neutrophil fate in CF. Recent studies have underscored the importance of neutrophils in innate immunity and their functions appear to extend far beyond their well-described role in antibacterial defense. Perhaps a disturbance in neutrophil reprogramming during the course of an infection severely modulates the inflammatory response in CF. Furthermore there is an emerging concept that the CFTR itself may be an immune modulator and stimulating CFTR function in CF patients could promote neutrophil and macrophages antimicrobial function. Fostering the resolution of inflammation by favoring neutrophil apoptosis could preserve their microbicidal activities but decrease their proinflammatory potential. In this context, triggering neutrophil apoptosis with roscovitine may be a potential therapeutic option and this is currently being evaluated in CF patients. In the present review we discuss how neutrophils functions are disturbed in CF and how this may relate to chronic infection with P. aeuginosa and we propose novel research directions aimed at modulating neutrophil survival, dampening lung inflammation and ultimately leading to an amelioration of the lung disease.http://journal.frontiersin.org/article/10.3389/fcimb.2017.00243/fullinflammationcystic fibrosisPseudomonasPCNAapoptosishypoxia |
| spellingShingle | Benoît S. Marteyn Benoît S. Marteyn Benoît S. Marteyn Pierre-Régis Burgel Pierre-Régis Burgel Laurent Meijer Véronique Witko-Sarsat Véronique Witko-Sarsat Véronique Witko-Sarsat Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis Frontiers in Cellular and Infection Microbiology inflammation cystic fibrosis Pseudomonas PCNA apoptosis hypoxia |
| title | Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis |
| title_full | Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis |
| title_fullStr | Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis |
| title_full_unstemmed | Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis |
| title_short | Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis |
| title_sort | harnessing neutrophil survival mechanisms during chronic infection by pseudomonas aeruginosa novel therapeutic targets to dampen inflammation in cystic fibrosis |
| topic | inflammation cystic fibrosis Pseudomonas PCNA apoptosis hypoxia |
| url | http://journal.frontiersin.org/article/10.3389/fcimb.2017.00243/full |
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