Human cystic fibrosis monocyte derived macrophages display no defect in acidification of phagolysosomes when measured by optical nanosensors

Law, Sheonagh M.; Stanfield, Samuel J.; Hardisty, Gareth; Dransfield, Ian; Campbell, Colin J.; Gray, Robert D.

doi:10.1016/j.jcf.2019.09.003

Cited by 24 publications

(22 citation statements)

References 41 publications

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“…Although the chloride ion flux data have been interpreted to support a role for ClC7 (a Cl − /H + antiporter) in reacidification, 99 by and large the consensus from these studies is that cation counterion flux is key to lysosome acidification, and CFTR does not play a direct role. This is also supported by a more recent study using surface-enhanced Raman spectroscopy-based nanosensors showing that phagosomal acidification was the same for CF and non-CF MDMs, 100 although the authors argue that dynamics of bacterial phagocytosis may differ from that of nanosensors.…”

Section: The Contested Role Of Cftr In Phagosome Acidification: a Case Study To Highlight Interdisciplinary Contributionmentioning

confidence: 61%

Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Turton

Ingram

Valvano

2020

Journal of Leukocyte Biology

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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the homeostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respiratory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTR is, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitive to conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophages by affecting the lung milieu, but the mutations also appear to be directly consequential for intrinsic macrophage functions. Particular mutations can alter CFTR's folding, traffic of the protein to the membrane and function. As such, understanding the intrinsic effects of CFTR mutation requires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from the primary defect of CFTR dysfunction/absence. Investigations into CFTR's role in macrophages have exploited various models, each with their own advantages and limitations. This review summarizes these methodologic approaches, discussing their physiological correspondence and highlighting key findings. The controversy surrounding CFTR-dependent acidification is used as a case study to highlight difficulties in commensurability across model systems. Recent work in macrophage biology, including polarization and host-pathogen interaction studies, brought into the context of CFTR research, offers potential explanations for observed discrepancies between studies. Moreover, the rapid advancement of novel gene editing technologies and new macrophage model systems makes this assessment of the field's models and methodologies timely.

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Section: The Contested Role Of Cftr In Phagosome Acidification: a Case Study To Highlight Interdisciplinary Contributionmentioning

confidence: 61%

Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Turton

Ingram

Valvano

2020

Journal of Leukocyte Biology

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“…JID: JCF [m5G; November 16, 2021;14:0 ] ing of aberrant transgene expression in this mouse may also go some way to explaining certain anomalies in our understanding of macrophage function in CF more generally. Notably, the use of the gut-corrected Tg(FABP-hCFTR) CF mouse to propose Cftr -dependent regulation of phagosomal acidification as a key mechanism behind defective intracellular bacterial killing in CF macrophages was a major finding in the field, but spawned much controversy and has ultimately not proven reproducible despite the use of more accurate ratiometric methods with greater pH sensitivity than the fluorescein-based techniques employed in the original study [26][27][28] . One explanation for this ectopic transgene expression may be that murine macrophages express Fabp2 .…”

Section: Article In Pressmentioning

confidence: 99%

Macrophages from gut-corrected CF mice express human CFTR and lack a pro-inflammatory phenotype

Gillan

Hardisty

Davidson

et al. 2022

Journal of Cystic Fibrosis

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“…However, this role of the CFTR protein in controlling phagosomal pH is controversially discussed. Other authors showed that CFTR-deficient macrophage cell lines and primary mouse and human AMs display no change in the pH of phagosomes, partly related to the methods used to quantify phagolysosomal pH [ 69 ].…”

Section: The Cftr Protein: Not Just a Chloride Channelmentioning

confidence: 99%

CFTR Protein: Not Just a Chloride Channel?

Hanssens

Duchateau

Casimir

2021

Cells

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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl−) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na+) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl− and Na+ transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO3−, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF.

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Human cystic fibrosis monocyte derived macrophages display no defect in acidification of phagolysosomes when measured by optical nanosensors

Cited by 24 publications

References 41 publications

Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Macrophages from gut-corrected CF mice express human CFTR and lack a pro-inflammatory phenotype

CFTR Protein: Not Just a Chloride Channel?

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