Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation

Front Immunol. 2023 Nov 16:14:1242381. doi: 10.3389/fimmu.2023.1242381. eCollection 2023.

Abstract

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.

Keywords: CFTR; cystic fibrosis; lung infection and inflammation; macrophage-specific CF mouse model; single-cell RNA sequencing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis* / complications
  • Inflammation / pathology
  • Lung / pathology
  • Macrophages / pathology
  • Mice

Substances

  • Cystic Fibrosis Transmembrane Conductance Regulator