Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis

Gabillard-Lefort, Claudie; Casey, Michelle; Glasgow, Arlene; Boland, Fiona; Kerr, Orla; Marron, Elaine; Lyons, Anne-Marie; Gunaratnam, Cedric; McElvaney, Noel G.; Reeves, Emer P.

doi:10.1164/rccm.202106-1426oc

Cited by 34 publications

(35 citation statements)

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“…The deficiency of CFTR leads to reduced efflux chloride in epithelial cells, which contributes to bacterial proliferation and excessive inflammation in CF by forming a thick and viscous mucus layer [ 20 ]. Recently, it is reported that increased cytosolic chloride caused by dysfunction of CFTR induces the activation of the NLRP3 inflammasome in monocytes by upregulating the expression of P2X7R, which contributes to inflammation in CF.…”

Section: Pyroptosis and Inflammation-related Respiratory Diseasesmentioning

confidence: 99%

“…Recently, it is reported that increased cytosolic chloride caused by dysfunction of CFTR induces the activation of the NLRP3 inflammasome in monocytes by upregulating the expression of P2X7R, which contributes to inflammation in CF. While the CFTR modulators restore the CFTR expression and reduce inflammation in patients with CF by blocking the P2X7R/NLRP3/caspase-1 axis [ 20 ]. Additionally, the absence of CFTR leads to the upregulation of epithelial sodium channel (ENaC), which may be partially responsible for the recurrent respiratory infections and chronic inflammation in CF [ 61 ].…”

Section: Pyroptosis and Inflammation-related Respiratory Diseasesmentioning

confidence: 99%

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Pyroptosis in inflammation-related respiratory disease

Feng

Yangzhong

et al. 2022

J Physiol Biochem

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Pyroptosis is commonly induced by the gasdermin (GSDM) family and is accompanied by the release of inflammatory cytokines such as IL-1β and IL-18. Recently, increasing evidence suggests that pyroptosis plays a role in respiratory diseases. This review aimed to summarize the roles and mechanisms of pyroptosis in inflammation-related respiratory diseases. There are several pathways involved in pyroptosis, such as the canonical inflammasome-induced pathway, non-canonical inflammasome-induced pathway, caspase-1/3/6/7/GSDMB pathway, caspase-8/GSDMC pathway, caspase-8/GSDMD pathway, and caspase-3/GSEME pathway. Pyroptosis may be involved in asthma, chronic obstructive pulmonary disease (COPD), lung cancer, acute lung injury (ALI), silicosis, pulmonary hypertension (PH), and tuberculosis (TB), in which the NLRP3 inflammasome-induced pathway is mostly highlighted. Pyroptosis contributes to the deterioration of asthma, COPD, ALI, silicosis, and PH. In addition, pyroptosis has dual effects on lung cancer and TB. Additionally, whether pyroptosis participates in cystic fibrosis (CF) and sarcoidosis or not is largely unknown, though the activation of NLRP3 inflammasome is found in CF and sarcoidosis. In conclusion, pyroptosis may play a role in inflammation-related respiratory diseases, providing new therapeutic targets.

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Section: Pyroptosis and Inflammation-related Respiratory Diseasesmentioning

confidence: 99%

Section: Pyroptosis and Inflammation-related Respiratory Diseasesmentioning

confidence: 99%

Pyroptosis in inflammation-related respiratory disease

Feng

Yangzhong

et al. 2022

J Physiol Biochem

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“…Although the astonishing clinical results obtained by this combination therapy in eligible patients (approximately 90% of PWCF), its impact on overall immunity and the inflammatory components remains unclear. Recently, Gabillard-Lefort and colleagues investigated the effect of ELX/TEZ/IVA on the inflammatory ATP/P2 × 7R axis in CF monocytes [ 145 ]. Firstly, they demonstrated that the effect of extracellular ATP (eATP) on NLRP3-inflammasome activation involves the P2 purinergic receptor P2 × 7R (abundantly expressed on monocytes and macrophages) and that P2 × 7R expression is regulated by CFTR activity, explaining, at least in part, how excessive inflammation may be directly associated with CFTR dysfunction.…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

“…Firstly, they demonstrated that the effect of extracellular ATP (eATP) on NLRP3-inflammasome activation involves the P2 purinergic receptor P2 × 7R (abundantly expressed on monocytes and macrophages) and that P2 × 7R expression is regulated by CFTR activity, explaining, at least in part, how excessive inflammation may be directly associated with CFTR dysfunction. Lastly, they showed that ELX/TEZ/IVA, via the rescue of CFTR activity, corrected K + efflux, normalized intracellular Ca 2+ , and reduced P2 × 7R expression of CF monocytes with subsequent decreased NLRP3 expression, caspase-1 activation, and IL-1β secretion upon stimulation with LPS and ATP; moreover, the HEMT normalized plasma eATP and IL-1β levels of treated individuals [ 145 , 146 ]. Table 2 summarizes the effects of CFTR modulators on phagocytes.…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

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

Meoli

Eickmeier

Pisi

et al. 2022

IJMS

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Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.

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“…New Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators of defective protein are having a positive impact on Cystic Fibrosis (CF) care [1] . F508del-CFTR pwCF treated with the potent modulator Trikafta (Kaftrio) feel significant benefits of lung function with reduction of inflammatory markers [2] . Whether mutant CFTR modulators are sufficient to completely halt and report to healthy baseline levels lung inflammation in pwCF adults and adolescents with advanced lung disease is presently under scrutiny and novel anti-inflammatory strategies continue to be proposed (for update see Editorial [3] and the related Research Topic collection of articles).…”

mentioning

confidence: 99%