CFTR is required for zinc-mediated antibacterial defense in human macrophages - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Proceedings of the National Academy of Sciences of the United States of America Year : 2024

CFTR is required for zinc-mediated antibacterial defense in human macrophages

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa . Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli -induced zinc accumulation and zinc vesicle formation in these cells, and E . coli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli . Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against E . coli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa , used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF.
Fichier principal
Vignette du fichier
2024_Das-Gupta_PNAS_vol-121.pdf (763.45 Ko) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Licence : CC BY NC ND - Attribution - NonCommercial - NoDerivatives

Dates and versions

hal-04466109 , version 1 (21-02-2024)

Licence

Attribution - NonCommercial - NoDerivatives

Identifiers

Cite

Kaustav das Gupta, James Curson, Abdullah Tarique, Ronan Kapetanovic, Mark Schembri, et al.. CFTR is required for zinc-mediated antibacterial defense in human macrophages. Proceedings of the National Academy of Sciences of the United States of America, 2024, 121 (8), pp.e2315190121. ⟨10.1073/pnas.2315190121⟩. ⟨hal-04466109⟩
46 View
8 Download

Altmetric

Share

Gmail Facebook X LinkedIn More