Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages
Abstract Macrophage dysfunction has been well-described in Cystic Fibrosis (CF) and may contribute to bacterial persistence in the lung. Whether CF macrophage dysfunction is related directly to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in macrophages or an indirect consequence of ch...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-38300-9 |
| _version_ | 1797769556733722624 |
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| author | Daniel S. Aridgides Diane L. Mellinger Lorraine L. Gwilt Thomas H. Hampton Dallas L. Mould Deborah A. Hogan Alix Ashare |
| author_facet | Daniel S. Aridgides Diane L. Mellinger Lorraine L. Gwilt Thomas H. Hampton Dallas L. Mould Deborah A. Hogan Alix Ashare |
| author_sort | Daniel S. Aridgides |
| collection | DOAJ |
| description | Abstract Macrophage dysfunction has been well-described in Cystic Fibrosis (CF) and may contribute to bacterial persistence in the lung. Whether CF macrophage dysfunction is related directly to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in macrophages or an indirect consequence of chronic inflammation and mucostasis is a subject of ongoing debate. CFTR modulators that restore CFTR function in epithelial cells improve global CF monocyte inflammatory responses but their direct effects on macrophages are less well understood. To address this knowledge gap, we measured phagocytosis, metabolism, and cytokine expression in response to a classical CF pathogen, Pseudomonas aeruginosa in monocyte-derived macrophages (MDM) isolated from CF F508del homozygous subjects and nonCF controls. Unexpectedly, we found that CFTR modulators enhanced phagocytosis in both CF and nonCF cohorts. CFTR triple modulators also inhibited MDM mitochondrial function, consistent with MDM activation. In contrast to studies in humans where CFTR modulators decreased serum inflammatory cytokine levels, modulators did not alter cytokine secretion in our system. Our studies therefore suggest modulator induced metabolic effects may promote bacterial clearance in both CF and nonCF monocyte-derived macrophages. |
| first_indexed | 2024-03-12T21:10:47Z |
| format | Article |
| id | doaj.art-3499643d88e04029a4169251b68131a1 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-12T21:10:47Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3499643d88e04029a4169251b68131a12023-07-30T11:11:57ZengNature PortfolioScientific Reports2045-23222023-07-0113111110.1038/s41598-023-38300-9Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophagesDaniel S. Aridgides0Diane L. Mellinger1Lorraine L. Gwilt2Thomas H. Hampton3Dallas L. Mould4Deborah A. Hogan5Alix Ashare6Section of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical CenterSection of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical CenterSection of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical CenterDepartment of Microbiology and Immunology, Dartmouth College, Geisel School of MedicineDepartment of Microbiology and Immunology, Dartmouth College, Geisel School of MedicineDepartment of Microbiology and Immunology, Dartmouth College, Geisel School of MedicineSection of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical CenterAbstract Macrophage dysfunction has been well-described in Cystic Fibrosis (CF) and may contribute to bacterial persistence in the lung. Whether CF macrophage dysfunction is related directly to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in macrophages or an indirect consequence of chronic inflammation and mucostasis is a subject of ongoing debate. CFTR modulators that restore CFTR function in epithelial cells improve global CF monocyte inflammatory responses but their direct effects on macrophages are less well understood. To address this knowledge gap, we measured phagocytosis, metabolism, and cytokine expression in response to a classical CF pathogen, Pseudomonas aeruginosa in monocyte-derived macrophages (MDM) isolated from CF F508del homozygous subjects and nonCF controls. Unexpectedly, we found that CFTR modulators enhanced phagocytosis in both CF and nonCF cohorts. CFTR triple modulators also inhibited MDM mitochondrial function, consistent with MDM activation. In contrast to studies in humans where CFTR modulators decreased serum inflammatory cytokine levels, modulators did not alter cytokine secretion in our system. Our studies therefore suggest modulator induced metabolic effects may promote bacterial clearance in both CF and nonCF monocyte-derived macrophages.https://doi.org/10.1038/s41598-023-38300-9 |
| spellingShingle | Daniel S. Aridgides Diane L. Mellinger Lorraine L. Gwilt Thomas H. Hampton Dallas L. Mould Deborah A. Hogan Alix Ashare Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages Scientific Reports |
| title | Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages |
| title_full | Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages |
| title_fullStr | Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages |
| title_full_unstemmed | Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages |
| title_short | Comparative effects of CFTR modulators on phagocytic, metabolic and inflammatory profiles of CF and nonCF macrophages |
| title_sort | comparative effects of cftr modulators on phagocytic metabolic and inflammatory profiles of cf and noncf macrophages |
| url | https://doi.org/10.1038/s41598-023-38300-9 |
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