Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill <i>Pseudomonas aeruginosa</i>

Barnaby, Roxanna; Koeppen, Katja; Nymon, Amanda B.; Hampton, Thomas H.; Berwin, Brent; Ashare, Alix; Stanton, Bruce A.

doi:10.1152/ajplung.00461.2017

Cited by 62 publications

(71 citation statements)

References 35 publications

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“…Ivacaftor may be acting by a CFTR-dependent mechanism, as has been described for other cystic fibrosis-related myeloid cell defects [11,12]. Ivacaftor could also act directly on monocytes by a CFTR-independent mechanism; recent studies observed that CFTR modulators may have immune-dampening effects on macrophages that lack modulator-susceptible CFTR mutations [12,13]. Finally, reduced monocyte IFN-γ responses could be a secondary effect of ivacaftor.…”

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confidence: 90%

Ivacaftor decreases monocyte sensitivity to interferon-γ in people with cystic fibrosis

et al. 2020

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Management of cystic fibrosis has been revolutionised by the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. These compounds treat the underlying molecular basis of the disease by increasing activity of defective CFTR channels, which improves many clinical parameters and enhances patient quality of life [1]. Next-generation modulators, also known as triple combination therapy, promise to be highly efficacious in up to 90% of patients [2] and will likely dramatically change the landscape of cystic fibrosis disease. Studies examining individuals before and after initiation of CFTR modulators have revealed novel functions of CFTR and shown that CFTR modulators do not reverse all disease manifestations [3-5]. Thus, knowledge of the post-modulator cystic fibrosis disease state is crucial for understanding what continued therapies will be needed for people with cystic fibrosis and what new challenges may arise. In prior work, we sought to identify immune pathways that were differentially modulated in the presence and absence of CFTR activity [6]. We isolated monocytes from subjects with G551D-CFTR mutations before and after initiation of the modulator ivacaftor. Using an unbiased proteomics approach, we identified post-ivacaftor changes in the monocyte plasma membrane proteome consistent with decreased interferon (IFN)-γ-related responses. Although both monocytes and macrophages from individuals with cystic fibrosis have been shown to manifest abnormal immune responses, myeloid IFN-γ responses had not previously been reported as altered in people with cystic fibrosis [7]. In the current study, we took advantage of a second cohort of subjects with cystic fibrosis who were initiating ivacaftor to test the hypothesis that ivacaftor dampens monocyte sensitivity to IFN-γ.

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Ivacaftor decreases monocyte sensitivity to interferon-γ in people with cystic fibrosis

et al. 2020

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“…In addition to neutrophils, the beneficial effects of CFTR modulators were also demonstrated on MDMs from people with CF ex vivo. Barnaby et al studied the effects of lumacaftor alone or in combination with ivacaftor on the ability of human F508del/F508del MDMs to phagocytose and kill P aeruginosa . Lumacaftor alone restored the ability of CF MDMs to phagocytose and kill P aeruginosa to levels observed in MDMs obtained from non‐CF subjects.…”

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

“…Although lumacaftor alone had no significant effect on P aeruginosa ‐stimulated cytokine secretion by CF MDMs, ivacaftor alone or ivacaftor in combination with lumacaftor significantly reduced secretion of several proinflammatory cytokines, including IL‐6, IL‐8, TNF‐α, IFN‐γ, and GM‐CSF. The authors speculated that the clinical efficacy of lumacaftor/ivacaftor may have been due to the ability of lumacaftor to stimulate phagocytosis and killing of P aeruginosa by macrophages . The fact that the inflammatory response in cells isolated from people with CF and studied ex vivo was attenuated by the administration of CFTR modulators indicates that CF inflammation is not entirely effective or beneficial, but it may be related to the underlying basic defect.…”

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

“…50 In a subsequent study, neither to stimulate phagocytosis and killing of P aeruginosa by macrophages. 54 The fact that the inflammatory response in cells isolated from people with CF and studied ex vivo was attenuated by the administration of CFTR modulators indicates that CF inflammation is not entirely effective or beneficial, but it may be related to the underlying basic defect.…”

Section: S33mentioning

confidence: 99%

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Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

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“…Indeed, the corrector VX809 does not produce an effect on proinflammatory cytokines production by macrophages exposed to P. aeruginosa while stimulating their phagocytosis activity. In contrast, the potentiator VX770 reduces proinflammatory cytokines but inhibits macrophages’ phagocytosis activity ( Barnaby et al, 2018 ). VX809 alone or in combination with VX770 does not affect pro-inflammatory cytokines production by CF airway epithelial cells.…”

Section: Cf Airway Disease Treatments and Inflammationmentioning

confidence: 99%

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

2020

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Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients’ lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.

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Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa

Cited by 62 publications

References 35 publications

Ivacaftor decreases monocyte sensitivity to interferon-γ in people with cystic fibrosis

Ivacaftor decreases monocyte sensitivity to interferon-γ in people with cystic fibrosis

Inflammation in cystic fibrosis: An update

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

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