Abstract
Background Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host–pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes.
Methods Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed.
Results ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m−2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride.
Conclusion ETI is associated with unique changes in innate immune function and clinical outcomes.
Abstract
Elexacaftor/tezacaftor/ivacaftor partially restores CFTR expression and function in CF macrophages. Macrophage CFTR restoration correlates with clinical outcomes. Results are individualised, reflecting donor genotypic and phenotypic variation. https://bit.ly/3dqSWfO
Footnotes
Author contributions: S. Zhang and C.L. Shrestha performed scientific experiments, study design and analysis, and edited and wrote a portion of the manuscript. F. Robledo-Avila performed patch-clamp, assisted with experiments and edited the manuscript. D. Jaganathan, B.L. Wisniewski and N. Brown assisted with scientific experiments and edited the manuscript. H. Pham collected participant samples and edited the manuscript. K. Carey isolated human cells and edited the manuscript. A.O. Amer, L. Hall-Stoodley and K.S. McCoy assisted with grant support, data analysis and editing of the manuscript. S. Bai assisted with statistical analysis. S. Partida-Sanchez assisted with experiments, data analysis and editing of the manuscript. B.T. Kopp acquired grant support, designed the study, oversaw recruitment, analysed data and wrote the manuscript.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00216-2023
Conflict of interest: The authors declare that no conflicts of interest exists.
Support statement: This study was supported by CF Foundation grants KOPP16I0 (B.T. Kopp), PARTID18P0 (S. Partida-Sanchez), HALLST18I0 (L. Hall-Stoodley), NIH R01 HL158747 (B.T. Kopp, S. Partida-Sanchez, A.O. Amer and L. Hall-Stoodley), NIH R01 HL148171 (B.T. Kopp), NIH R01 AI24121 (A.O. Amer) and NIH R01 HL127651 (A.O. Amer). This work was supported in part by the Cure CF Columbus Research and Development Program (C3RDP) Cores including the Translational Core (C3TC) and Immune Core (C3IC). C3RDP is supported by the Division of Pediatric Pulmonary Medicine, the Biopathology Center Core and the Data Collaboration Team at Nationwide Children's Hospital. Grant support provided by The Ohio State University Center for Clinical and Translational Science (National Center for Advancing Translational Sciences; UL1TR002733) and by the CF Foundation (MCCOY19RO). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 4, 2021.
- Accepted September 16, 2022.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org