Cystic fibrosis (CF) is characterised by repeated pulmonary infections and disordered innate immune-driven inflammation. The relationship between these two key drivers of disease progression remain poorly understood. We and others have recently provided evidence supporting the hypothesis that the NLRP3-inflammasome is a key regulator of inflammation in CF (McElvaney et al., 2019; Peckham et al., 2017; Scambler et al., 2019). We’ve demonstrated that both CF epithelia and monocytes/serum from patients with CF exhibit an enhanced pro-inflammatory signature when compared with healthy controls and patients with non-CF bronchiectasis. We observed CF-specific increases in IL-18, IL-1β, caspase-1 activity, in addition to ASC-speck release, that were all reversed by pre-treatment with epithelial sodium channel (ENaC) and NLRP3-inflammasome inhibitors (Peckham et al., 2017; Scambler et al., 2019). In this paper, we examine the therapeutic potential of controlling inflammation with CFTR modulators. These small molecules are known to correct CFTR dysfunction and partially restore CFTR-mediated ENaC inhibitory activity (Cholon et al., 2014; Pranke et al., 2017).

The NLRP3-inflammasome senses multiple damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Amongst the latter, lipopolysaccharide (LPS) is a major component of the outer membrane of two of the main pathogens found in CF airways, the gram-negative bacteriae such a Pseudomonas aeruginosa (P. aeruginosa) and members of the Burkholderia cepacia complex (B. cenocepacia). It has been reported that the latter organism can trigger the NLRP3-inflammasome and exacerbate the proinflammatory response, both through inflammasome activation and IL-1β/IL-18 processing (Rimessi et al., 2015; Gavrilin et al., 2012; Rosales-Reyes et al., 2012). In this regard, in both murine and human CF, NLRP3 activity contributes to IL-1β-dependent inflammation which can be negatively regulated by anakinra, an IL-1 receptor antagonist (IL-1Ra) (McElvaney et al., 2019; Iannitti et al., 2016). In mice, the NLRP3 inhibitor, MCC950, reduces IL-1β levels in the lungs, decreases airway inflammation and improves airway clearance of P. aeruginosa (McElvaney et al., 2019). Thus, defective CFTR expression and function appears to be driving inflammation, by lowering the threshold of innate immune defences and reducing the ability of myeloid cells, such as neutrophils and macrophages to resolve infection and inflammation (Barnaby et al., 2018; Bonfield et al., 2012). Conditional inactivation of Cftr in myeloid cells of mice resulted in a dysfunctional immune response, with Cftr-lacking mice taking longer to resolve inflammation and to rectify infection, when compared to wild-type (WT) mice (Bonfield et al., 2012). Finally, in young children with CF, inflammation can be detected in bronchoalveolar lavage (BAL) fluid, in the absence of infection, and this process is mainly driven via NLRP3-inflammasome activation (Rosenow et al., 2019; McElvaney et al., 2018).

The introduction of CFTR modulators into clinical practice has resulted in a paradigm shift in therapeutic options, whereby targeting the clinico-pathogenic origin of the defective CFTR rather than the secondary effects of CFTR dysfunction has become a reality (VX17-445-103 Trial Group et al., 2019; VX17-445-102 Study Group et al., 2019; VX08-770-102 Study Group et al., 2011; Taylor-Cousar et al., 2017; TRAFFIC Study Group et al., 2015). These drug regimens were primarily developed to improve cell-surface expression and function of the CFTR anion channel but there are limited data on whether they can directly modulate CF-related inflammation (Barnaby et al., 2018; Hisert et al., 2017). Treatment of primary bronchial epithelial cell cultures (BECs), bearing two Phe508del mutations, with the combination of ivacaftor/lumacaftor (IVA/LUM) depresses CXCL8 transcription, p38 MAPK phosphorylation and reduces serum levels of several proinflammatory cytokines, in response to P. aeruginosa (Barnaby et al., 2018; Ruffin et al., 2018). Treatment with the single agent, ivacaftor, currently approved for patients with gating mutations, such as G551D, has also been reported to reduce sputum levels of neutrophil elastase, IL-8, and IL-1β (VX08-770-102 Study Group et al., 2011; Hisert et al., 2017), and these changes may reflect improved clinical health rather than a direct anti-inflammatory consequence of increased CFTR function.

The aims of our study were firstly, to assess whether CFTR modulators could directly downregulate the increased serum and (innate-immune) cell-derived IL-1β and IL-18 cytokine signature in cells harvested from adults with CF, and secondly, to explore differences in response between drug regimens as a guide to inform future studies.

There is an ongoing debate as to whether correcting the primary ion transport defect, with CFTR modulators alone, can resolve both infection and inflammation, two key components driving CF lung pathology. As a result several novel anti-inflammatory agents are now being developed with the aim of slowing down disease progression (Cystic Fibrosis Foundation, 2020). As recurrent episodes of CF inflammation are the direct result of CFTR dysfunction, it follows that correcting CFTR itself should influence the aberrant changes in innate immunity present in CF, and downregulate the self-propagating inflammatory response (Mesureur et al., 2017).

The present study provides evidence of differential downstream regulation of inflammation, in vivo, following short term administration of IVA/LUM or IVA/TEZ. We observed a direct effect of CFTR modulators in both serum and NLRP3-stimulated PBMCs. Treatment with either IVA/LUM or IVA/TEZ significantly reduced serum and NLRP3-stimulated IL-18levels, TNF secretion and caspase-1 activity. There was also an increase in serum IL-10, which is a potent anti-inflammatory cytokine that downregulates the inflammatory response and ameliorates immunopathology (Asadullah et al., 2003). Only IVA/TEZ significantly reduced serum and NLRP3-stimulated IL-1β secretion and pro-IL-1β, mRNA transcripts. This difference is potentially important, as IL-1β is significantly elevated in CF and has a wide range of biological effects, associated with both infection and inflammation. Similar differences were also seen following the addition of IVA/TEZ drug to monocytes isolated from clinically stable ‘drug-naïve’ CF patients, homozygous for Phe508del.

Both LUM and TEZ exert their clinical effects by increasing the processing and trafficking of mature CFTR protein to the cell surface. When combined with the potentiator, IVA, they partially rectify CFTR function and alter CFTR-ENaC coupling, which results in the inhibition of the elevated amiloride-sensitive sodium transport that is characteristic of CF (Cholon et al., 2014; Pranke et al., 2017). Studies of nasal potential differences and rectal intestinal current measurements (ICM) studies suggest that dual combination therapy rescue Phe508del CFTR, by approximately 10% to 18% of normal, with both drugs having a similar effect on ion transport (Gentzsch and Mall, 2018; Graeber et al., 2018). The disparity in IL-1β secretion was, therefore, surprising and may result from off-target effects, which have been reported with CFTR modulators. For instance, IVA can influence various solute carriers in vitro and reduce the stability of LUM-rescued Phe508del-CFTR (Chin et al., 2018). Clinically, IVA/LUM has also been associated with unexplained increased respiratory adverse events, which can occur relatively acutely after starting treatment. Symptoms include dyspnoea and chest tightness, features which have not been reported with IVA/TEZ (Habib et al., 2019). It might also be the case that pharmacokinetics of LUM and TEZ may differ.

During this study, combination therapy was only available through a Vertex compassionate use program, with treatment inclusion criteria including lung transplant assessment and a ppFEV1 <40%, for at least two months. This is in contrast to reported phase three clinical trials which recruited stable patients with significantly higher lung function. In those studies, treatment over a 24 week period resulted in modest but significant improvements in lung function of around 3%, with reduced pulmonary exacerbations and a decrease in annual rate of ppFEV1 decline vs matched controls (Konstan et al., 2016). Furthermore, in adults with severe obstructive lung disease receiving IVA/LUM, significant improvements in FEV₁ can be absent in the first six months of treatment (Wark et al., 2019). While our study was not designed to investigate clinical efficacy, the absence of significant changes in clinical parameters, during our three month study period, was consistent with stable disease rather than a decline in health, as might be expected in a population with severe lung disease.

The association between CF and increased secretion of both IL-18 and IL-1β, as well as pro-IL-1β mRNA transcripts, may suggest that inhibiting IL-1β alone, with drugs such as anakinra, an IL-1 receptor antagonist, may prove less effective than drugs which target CFTR and, thereby, modify both IL-18 and IL-1β secretion. However baseline IL-1β levels remained elevated and additional targeting of the IL-1 receptor, could significantly enhance clinical effect, especially in patients on IVA/LUM where IL-1β was not significantly downregulated.

The effect of IVA/LUM and IVA/TEZ was lost at 36 hr post-oral therapy, but was regained following re-incubation with the corresponding drugs in vitro. This suggests that the anti-inflammatory properties of CFTR modulators can be prolonged, when drug levels are sustained through in vitro administration, but also highlights the additional effect of CFTR modulators on pro-inflammatory cytokine levels. This finding has potential implications for patients who struggle with compliance, as missing a single dose will influence inflammatory cytokine levels, and may lead to unwanted side-effects as well as influencing the effectiveness of the therapy (Abbott and Bilton, 2015).

From this study, it seems that IL-18 and IL-1β are the most reliable biomarkers to inform drug effectiveness at downregulating inflammation in CF. Although TNF is not elevated in serum or PBMCs from CF relative to HC (Figure 2—figure supplement 2, C), it has been shown by independent research groups, that the CFTR is actively involved in the regulation of TNF, via the NF- κB pathway in lung epithelial cells (Hunter et al., 2010; Vij et al., 2009). For example, transient-transfection of WT CFTR into CFTR-naive H441 lung epithelial cells, dose-dependently down-regulates both the basal and TNF evoked NF-κB activity (Hunter et al., 2010).

Some consideration should also be given to other biomarkers, such as IL-6, which did not change significantly with treatment and to the anti-inflammatory IL-10 cytokine which rose significantly and may help discriminate individual and drug specific responses in future studies.

In summary, systemic inflammation plays a major role in the pathogenesis of CF and, to our knowledge, this pilot study is the first to demonstrate that CFTR modulators have potent innate anti-inflammatory properties, that can be measured in the clinic, both ex vivo and in vitro. Differences in drug effects on regulation of the inflammatory response highlight the importance of optimising biomarkers of inflammation, when assessing their individual treatment efficacy, which can substantially vary between patients. The introduction of newer, and more effective, drug combinations may prove highly efficacious at normalising the inflammatory response in CF, with the prospect of controlling disease progression. We believe our approach creates a template for a candidate cytokine protocol for future evaluation in CF trials of dysregulated inflammation in CF.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Heledd H Jarosz-Griffiths

   1. Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
   2. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Thomas Scambler

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5154-4815

2. Thomas Scambler

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft

   Contributed equally with

   Heledd H Jarosz-Griffiths

   Competing interests

   No competing interests declared

3. Chi H Wong

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2108-1615

4. Samuel Lara-Reyna

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9986-5279

5. Jonathan Holbrook

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Fabio Martinon

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

   Contribution

   Resources, Funding acquisition

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6969-822X

7. Sinisa Savic

   1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
   3. Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds, United Kingdom

   Contribution

   Supervision, Funding acquisition, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7910-0554

8. Paul Whitaker

   Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

9. Christine Etherington

   Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

10. Giulia Spoletini

    Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

    Contribution

    Resources

    Competing interests

    No competing interests declared

11. Ian Clifton

    Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

    Contribution

    Resources

    Competing interests

    No competing interests declared

12. Anil Mehta

    Division of Medical Sciences, University of Dundee, Dundee, United Kingdom

    Contribution

    Formal analysis, Supervision, Validation, Visualization, Writing - original draft, Writing - review and editing

    Competing interests

    No competing interests declared

13. Michael F McDermott

    1. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
    2. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

    Contribution

    Conceptualization, Supervision, Funding acquisition, Validation, Visualization, Project administration, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-1015-0745

14. Daniel Peckham

    1. Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
    2. Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
    3. Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds, United Kingdom

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Project administration, Writing - review and editing

    For correspondence

    D.G.Peckham@leeds.ac.uk

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7723-1868

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