Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic inflammation and decline in lung function are major reasons for morbidity in CF. Mutant CFTR expressed in phagocytic cells such as macrophages contributes to persistent infection, inflammation, and lung disease in CF. Macrophages play a central role in innate immunity by eliminating pathogenic microbes by a process called phagocytosis. Phagocytosis is required for tissue homeostasis, balancing inflammation, and crosstalk with the adaptive immune system for antigen presentation. This review focused on (1) current understandings of the signaling underlying phagocytic mechanisms; (2) existing evidence for phagocytic dysregulation in CF; and (3) the emerging role of CFTR modulators in influencing CF phagocytic function. Alterations in CF macrophages from receptor initiation to phagosome formation are linked to disease progression in CF. A deeper understanding of macrophages in the context of CFTR and phagocytosis proteins at each step of phagosome formation might contribute to the new therapeutic development of dysregulated innate immunity in CF. Therefore, the review also indicates future areas of research in the context of CFTR and macrophages.

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

“…Alveolar macrophages are the dominant immune cell in the steady state and conduct several functions: ensure and modulate the inflammatory response, either directly or by the crosstalk with the adaptive immune system, actualize the bacterial killing through a complex mechanism called phagocytosis, maintain tissue homeostasis acting as scavenger cells, and participate in regeneration processes [ 32 , 33 ]. The ability to promote all these functions is due to their plasticity.…”

“…Bonfield et al reached the same conclusions using an in vivo mouse model, showing that defective myeloid CFTR contributes to increased inflammation with elevated cytokine production, the recruitment of neutrophils, and the inability to resolve infection even in presence of functional epithelial CFTR [ 45 ]. However, in the case of CFTR dysfunction, the macrophage function is not only affected at the level of the promoted altered inflammatory response but also at the level of the phagocytosis and autophagy processes [ 32 , 46 ]. When a pathogen is encountered, alveolar macrophages initiate the immune response releasing cytokines and chemokines and recruiting neutrophils and monocyte-derived macrophages (MDMs) that drive inflammation; specifically, MDMs are recruited through the release of monocyte chemoattractant protein-1 (MCP-1/CCL2) by macrophages that can also impact leukocyte behavior, influencing adhesion, polarization, effector molecule secretion, autophagy, killing, and survival [ 32 , 47 ].…”

“…Specifically, it is defective in CF airways because of the depletion of the autophagy-related protein Beclin 1 (BECN1) with consequent accumulation of SQSTM1/p62 substrate which promotes a pro-inflammatory status sequestering misfolded ubiquitinated F508del-CFTR and anti-inflammatory proteins, such as PPARγ and IK-Bα. In their study, Ferrari et al demonstrated that the proteostasis regulator cysteamine, which restores the function of F508del-CFTR mutant, reestablished the autophagy mechanism of CF MDMs, restoring both bacterial internalization and clearance of P. aeruginosa through a process that involves upregulation of BECN1 [ 31 , 32 , 46 ].…”

Distribution and Characteristics of Bacteria Isolated from Cystic Fibrosis Patients with Pulmonary Exacerbation

“…Among the P. aeruginosa isolates, 71.6% (43/60) showed a mucoid phenotype and were mostly isolated from patients older than 16 years of age (Figures 3(c) and 3(d)). Fourteen patients (patient numbers 4,6,10,14,19,20,23,30,43,85,86, 96, and 98) were infected with two or three morphotypes of P. aeruginosa with a diference in being mucoid/nonmucoid, pigment production, and/or diferent antibiotic susceptibility pattern (supplementary Table 3). Accordingly, 60 morphotypes of P. aeruginosa were evaluated for further investigations.…”

“…The accumulated mucus creates an appropriate niche for bacterial colonization and the development of persistent pulmonary bacterial infections [ 2 , 5 ]. This malicious cycle of chronic infection, inflammation, and tissue destruction results in a progressive decline in lung function, which is the primary cause of morbidity and mortality in patients with CF [ 6 ]. In addition to chronic lung infections, CF patients also experience recurrent episodes of acute decline in pulmonary function called “pulmonary exacerbation” (PE).…”