Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airwa...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1242381/full |
| _version_ | 1797626629066850304 |
|---|---|
| author | Dianne Wellems Yawen Hu Scott Jennings Guoshun Wang |
| author_facet | Dianne Wellems Yawen Hu Scott Jennings Guoshun Wang |
| author_sort | Dianne Wellems |
| collection | DOAJ |
| description | Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood. Here, we report that loss of CFTR function in macrophages causes extended lung inflammation. After intratracheal inoculation with Pseudomonas aeruginosa, mice with a macrophage-specific Cftr-knockout (Mac-CF) were able to mount an effective host defense to clear the bacterial infection. However, three days post-inoculation, Mac-CF lungs demonstrated significantly more neutrophil infiltration and higher levels of inflammatory cytokines, suggesting that Mac-CF mice had a slower resolution of inflammation. Single-cell RNA sequencing revealed that absence of CFTR in the macrophages altered the cell transcriptional program, affecting the cell inflammatory and immune responses, antioxidant system, and mitochondrial respiration. Thus, loss of CFTR function in macrophages influences cell homeostasis, leading to a dysregulated cellular response to infection that may exacerbate CF lung disease. |
| first_indexed | 2024-03-11T10:12:54Z |
| format | Article |
| id | doaj.art-84f416a6af26408aa47163bbe9abce14 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T10:12:54Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-84f416a6af26408aa47163bbe9abce142023-11-16T13:52:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12423811242381Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammationDianne WellemsYawen HuScott JenningsGuoshun WangCystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood. Here, we report that loss of CFTR function in macrophages causes extended lung inflammation. After intratracheal inoculation with Pseudomonas aeruginosa, mice with a macrophage-specific Cftr-knockout (Mac-CF) were able to mount an effective host defense to clear the bacterial infection. However, three days post-inoculation, Mac-CF lungs demonstrated significantly more neutrophil infiltration and higher levels of inflammatory cytokines, suggesting that Mac-CF mice had a slower resolution of inflammation. Single-cell RNA sequencing revealed that absence of CFTR in the macrophages altered the cell transcriptional program, affecting the cell inflammatory and immune responses, antioxidant system, and mitochondrial respiration. Thus, loss of CFTR function in macrophages influences cell homeostasis, leading to a dysregulated cellular response to infection that may exacerbate CF lung disease.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1242381/fullcystic fibrosisCFTRmacrophage-specific CF mouse modellung infection and inflammationsingle-cell RNA sequencing |
| spellingShingle | Dianne Wellems Yawen Hu Scott Jennings Guoshun Wang Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation Frontiers in Immunology cystic fibrosis CFTR macrophage-specific CF mouse model lung infection and inflammation single-cell RNA sequencing |
| title | Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation |
| title_full | Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation |
| title_fullStr | Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation |
| title_full_unstemmed | Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation |
| title_short | Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation |
| title_sort | loss of cftr function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation |
| topic | cystic fibrosis CFTR macrophage-specific CF mouse model lung infection and inflammation single-cell RNA sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1242381/full |
| work_keys_str_mv | AT diannewellems lossofcftrfunctioninmacrophagesaltersthecelltranscriptionalprogramanddelayslungresolutionofinflammation AT yawenhu lossofcftrfunctioninmacrophagesaltersthecelltranscriptionalprogramanddelayslungresolutionofinflammation AT scottjennings lossofcftrfunctioninmacrophagesaltersthecelltranscriptionalprogramanddelayslungresolutionofinflammation AT guoshunwang lossofcftrfunctioninmacrophagesaltersthecelltranscriptionalprogramanddelayslungresolutionofinflammation |