4.7 Article

CFTR Modulators Restore Acidification of Autophago-Lysosomes and Bacterial Clearance in Cystic Fibrosis Macrophages

Journal

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2022.819554

Keywords

autophagy; autophagosomes; lysosomal acidification; Burkholderia cenocepacia clearance; cystic fibrosis; CFTR modulators; autophago-lysosomes; macrophages

Funding

  1. NIAID [R01 AI24121]
  2. NHLBI [R01 HL12765101A1]
  3. Egyptian Bureau of Education
  4. Cure Cystic Fibrosis Columbus (C3)
  5. NIH T32 Infectious Disease Institute, Ohio State University
  6. Cystic Fibrosis Foundation
  7. Taawon Welfare Association
  8. Cystic Fibrosis Foundation [PARTID18P0]
  9. Cure CF Columbus Translational Core (C3TC)
  10. Division of Pediatric Pulmonary Medicine
  11. Biopathology Center Core
  12. Data Collaboration Team at Nationwide Children's Hospital
  13. Ohio State University Center for Clinical and Translational Science (National Center for Advancing Translational Sciences) [UL1TR002733]
  14. Cystic Fibrosis Foundation (Research Development Program) [MCCOY19RO]
  15. C3 Immune Core

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Cystic fibrosis (CF) macrophages show defects in clearing bacteria and autophagy process. CFTR is recruited to autophagosomes and improves autophagy flux, lysosomal acidification, function, and bacterial clearance. These findings clarify the role of CFTR in maintaining cellular acidification and autophagy process.
Cystic fibrosis (CF) human and mouse macrophages are defective in their ability to clear bacteria such as Burkholderia cenocepacia. The autophagy process in CF (F508del) macrophages is halted, and the underlying mechanism remains unclear. Furthermore, the role of CFTR in maintaining the acidification of endosomal and lysosomal compartments in CF cells has been a subject of debate. Using 3D reconstruction of z-stack confocal images, we show that CFTR is recruited to LC3-labeled autophagosomes harboring B. cenocepacia. Using several complementary approaches, we report that CF macrophages display defective lysosomal acidification and degradative function for cargos destined to autophagosomes, whereas non-autophagosomal cargos are effectively degraded within acidic compartments. Notably, treatment of CF macrophages with CFTR modulators (tezacaftor/ivacaftor) improved the autophagy flux, lysosomal acidification and function, and bacterial clearance. In addition, CFTR modulators improved CFTR function as demonstrated by patch-clamp. In conclusion, CFTR regulates the acidification of a specific subset of lysosomes that specifically fuse with autophagosomes. Therefore, our study describes a new biological location and function for CFTR in autophago-lysosomes and clarifies the long-standing discrepancies in the field.

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