Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

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Abstract

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

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Most cited references 23

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Interleukin-10 therapy--review of a new approach.

K Asadullah, W Sterry, H. Volk (2003)

Interleukin (IL)-10 is an important immunoregulatory cytokine produced by many cell populations. Its main biological function seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.

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IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

Rossana Iannitti, Valerio Napolioni, Vasilis Oikonomou … (2016)

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

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Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

Iwona M. Pranke, Aurélie Hatton, Juliette Simonin … (2017)

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

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Author and article information

Contributors

Daniel Peckham:

ORCID: https://orcid.org/0000-0001-7723-1868

Satyajit Rath: Role: Senior Editor

Jos WM van der Meer: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 02 March 2020

Publication date Collection: 2020

Volume: 9

Electronic Location Identifier: e54556

Affiliations

[1 ]Leeds Institute of Medical Research at St James's, University of Leeds LeedsUnited Kingdom

[2 ]Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds LeedsUnited Kingdom

[3 ]Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds LeedsUnited Kingdom

[4 ]Department of Biochemistry, University of Lausanne EpalingesSwitzerland

[5 ]Department of Clinical Immunology and Allergy, St James’s University Hospital LeedsUnited Kingdom

[6 ]Adult Cystic Fibrosis Unit, St James’s University Hospital LeedsUnited Kingdom

[7 ]Division of Medical Sciences, University of Dundee DundeeUnited Kingdom

Indian Institute of Science Education and Research (IISER) India

Radboud University Medical Centre Netherlands

Radboud University Netherlands

Author notes

[†]

These authors contributed equally to this work.

Author information

Heledd H Jarosz-Griffiths https://orcid.org/0000-0001-5154-4815

Chi H Wong http://orcid.org/0000-0003-2108-1615

Samuel Lara-Reyna http://orcid.org/0000-0002-9986-5279

Fabio Martinon http://orcid.org/0000-0002-6969-822X

Sinisa Savic http://orcid.org/0000-0001-7910-0554

Michael F McDermott http://orcid.org/0000-0002-1015-0745

Daniel Peckham https://orcid.org/0000-0001-7723-1868

Article

Publisher ID: 54556

DOI: 10.7554/eLife.54556

PMC ID: 7062465

PubMed ID: 32118580

SO-VID: ab36c863-e69d-404e-8f86-012629da293c

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 03 January 2020

Date accepted : 28 February 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000292, Cystic Fibrosis Trust;

Award ID: SRC009

Award Recipient : Daniel Peckham

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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Author impact statement CFTR modulators have potent innate anti-inflammatory properties that can be measured in clinic, both ex vivo and in vitro, which can be used to predict treatment efficacy.

ScienceOpen disciplines: Life sciences

Keywords: ivacaftor,lumacaftor,tezacaftor,cystic fibrosis,inflammation,nlrp3 inflammasome,human

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: ivacaftor, lumacaftor, tezacaftor, cystic fibrosis, inflammation, nlrp3 inflammasome, human

Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

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Most cited references 23

Interleukin-10 therapy--review of a new approach.

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

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