Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disease to affect Caucasian populations. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in reduced expression and function of the CFTR with the most common mutation (ΔF508/ΔF508) resulting in inadequate processing of the protein and subsequent intracellular trapping in the endoplasmic reticulum (ER) (Elborn, 2016). Clinical manifestations of this debilitating condition include repeated pulmonary infections, innate immune-driven episodes of inflammation and inflammatory arthritis (Elborn, 2016; Whitsett and Alenghat, 2015; Bals et al., 1999; Montgomery et al., 2017). The CFTR protein is widely expressed in a variety of cells and tissues where it functions as an anion channel, conducting chloride (Cl^-) and bicarbonate (HCO3-) ions, and as a regulator of a range of epithelial transport proteins, including the epithelial sodium channel (ENaC) (König et al., 2002; Konstas et al., 2003; Kunzelmann, 2003; Berdiev et al., 2009).

The NLRP3 inflammasome is an important inflammatory pathway in CF but there is little indication as to whether this reflects underlying innate autoinflammation or activation in response to chronic bacterial, viral and fungal infections, including pathogens such as Pseudomonas aeruginosa, and Burhkholderia cepacia complex (Iannitti et al., 2016; Rimessi et al., 2015; Montgomery et al., 2017; Fritzsching et al., 2015; Kiedrowski and Bomberger, 2018). We propose that CF exhibits many hallmarks of an autoinflammatory condition (Peckham et al., 2017; McGonagle and McDermott, 2006; McDermott et al., 1999), with infiltration by innate immune cells (macrophages and neutrophils) at target sites, and a lack of autoantibodies or autoreactive T cells (McDermott et al., 1999). The NLRP3 intracellular protein complex is a sensor that detects changes in cellular homeostasis rather than directly sensing common pathogenic or endogenous motifs. Multiple cellular events have been observed to trigger NLRP3 activation, including K⁺ efflux, Na⁺ influx, Cl^- efflux and Ca²⁺ signalling (Schorn et al., 2011; Muñoz-Planillo et al., 2013; Katsnelson and George, 2013; Domingo-Fernández et al., 2017; Green et al., 2018; Hafner-Bratkovič and Pelegrín, 2018). All known canonical inflammasomes, including the NLRP3 inflammasome, function as signalling platforms for caspase-1-driven activation of IL-1-type cytokines (IL-1β and IL-18). One of IL-18’s main functions is induction of cell-mediated immunity and IFN-γ secretion by natural killer (NK) and T-cells, whereas IL-1β has a central role in inducing fever with immune cell proliferation, differentiation and apoptosis. Inflammasome activation induces a programmed cell death downstream of the activation of caspases-1, 4, 5, and 11. Gasdermin D (GSDMD) is cleaved by said caspases, oligomerizing and forming pores (13 nm) in the plasma membrane, releasing mature IL-1β and IL-18 and triggering cell lysis, or pyroptosis (Cookson and Brennan, 2001; Platnich and Muruve, 2019).

In healthy lungs, ENaC helps maintain normal volume and composition of airway surface liquid (ASL). An absence or reduction in functional CFTR leads to defective CFTR-mediated anion transport and upregulation of ENaC. These changes in normal homeostasis result in fluid hyperabsorption, abnormally thick viscous mucus and defective mucociliary clearance (Althaus, 2013; Boucher, 2019). While there is no literature to support a direct link between ENaC and inflammation in CF, there is indirect evidence to suggest that aberrant sodium (Na⁺) transport influences the disease process. Overexpression of β-ENaC in mice, results in CF-like lung disease, with ASL dehydration, inflammation and mucous obstruction of bronchial airways (Mall et al., 2004; Zhou et al., 2011; Zhou et al., 2008). In humans, genetic variants in the β- and γ- ENaC chains, leading to functional abnormalities in ENaC, have been associated with bronchiectasis and CF-like symptoms (Fajac et al., 2008). By contrast, rare mutations associated with hypomorphic ENaC activity, can slow disease progression in patients homozygous for the CFTR ∆F508 mutation (Mall et al., 2004; Zhou et al., 2011; Donaldson and Boucher, 2007). These studies highlight the essential role of ENaC in regulating normal airway homeostasis and show that inhibition of ENaC may modify disease progression, either by altering ASL composition or modifying other processes, such as inflammation. Several trials are ongoing to assess the safety and effectiveness of new topical ENaC inhibitors to restoring airway surface liquid and mucociliary clearance in CF (Cystic Fibrosis Foundation, 2017).

The aims of this study were to characterise NLRP3 inflammasome activation in CF and to investigate the role of the epithelial Na⁺ channel, ENaC, in driving this inflammation through alterations in ionic homeostasis, a known NLRP3 activating event.

In order to fulfil these aims, monocytes and epithelial cells with characterised CF-associated mutations are directly compared to cohorts of NCFB and SAID.The NCFB cohort comprises of individuals with primary ciliary dyskinesia (PCD), a rare, ciliopathic, autosomal recessive genetic disorder affects the movement of cilia in the lining of the respiratory tract. Individuals with PCD suffer from reduced mucus clearance from the lungs, and susceptibility to chronic recurrent respiratory infections, as is the case with CF. By comparing monocytic- and epithelial-driven inflammation in CF and PCD, one is able to distinguish between inflammation due to recurrent infection, as is the case with both CF and NCFB, and inflammation that is downstream of CFTR/ENaC-mediated ionic disturbances, specific to CF.

The SAID patient cohort is composed of an array of systemic autoinflammatory diseases that are defined by an innate immune driven inflammation. The variety of autoinflammatory disorders described in this manuscript demonstrates the broad range of pathophysiology within this rare inflammatory disease spectrum. Here we demonstrate that the intrinsic ionic defect in cells and individuals with CF-associated mutations predisposes hyperactivation of the NLRP3 inflammasome, leading to inappropriate and destructive innate immune driven inflammation, as found in autoinflammation.

Here we have described our findings that IL-1-type cytokines were elevated in both monocytes and serum of patients with CF, but two of the major inflammasome-independent cytokines, TNF and IL-6, were not significantly elevated in these patients. In contrast to patients with SAID, these data suggest that the proinflammatory cytokine response in CF has a predominant NLRP3 inflammasome constitution. Furthermore, on NLRP3 inflammasome activation, IL-18 secretion was upregulated in the CF-associated mutant cell lines, IB3-1 (p<0.0001) and CuFi-1 (p<0.0001) relative to the BEAS-2B control, and these levels were reduced by treatment with small molecule inhibition of NLRP3 inflammasome signalling, thereby confirming the NLRP3 inflammasome as a major source of the elevated IL-18 inflammatory cytokine in these cells. Perhaps the most notable feature is the uncovering of a molecular link between enhanced ENaC-dependent Na+ influx, observed in cells with CF-associated mutations, and the exacerbated NLRP3 inflammasome activation. By pretreating these cells with CF-associated mutations with small molecule inhibitors of ENaC, the exaggerated IL-1-type cytokine response in vitro was diminished (Figure 7).

Figure 7

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Bronchial epithelial cell (BEC) lines can produce significant quantities of IL-18 on stimulation but secrete only negligible amounts of basal or stimulated IL-1β compared to hematopoietic cells (Tang et al., 2012; Peeters et al., 2013; Gillette et al., 2013). In human BEC models, rhinovirus has been associated with IL-1β release, a process accentuated by dual priming with both ATP and polyinosine polycytidylic acid (Poly I:C, which interacts with TLR3) (Piper et al., 2013; Shi et al., 2012). In general, IL-18 is the predominant cytokine secreted by non-myeloid cells, which are also capable of having activated inflammasomes (Okazawa et al., 2004). This contrasts with PBMCs, which produce large amounts of IL-1β, from both patients with CF and healthy controls (Tang et al., 2012). The differential secretion of IL-18 and IL-1β, observed in this study is noteworthy, with IL-1β secretion being undetectable in HBEC lines, under the conditions used. This disparity may reflect the function of these two inflammasome-processed zymogens; IL-18 is a cytokine that induces recruitment of neutrophils and Th17 differentiation, as well as IFNγ secretion, whereas IL-1β is an intrinsically more destructive cytokine, acting systemically to induce fever, proliferation, differentiation, apoptosis and sensitivity to pain. IL-1β secretion is tightly regulated by a highly controlled process, involving its own gene expression as well as inflammasome priming and assembly, whereas IL-18 is constitutively expressed and only depends on the two signals for inflammasome priming and assembly. In addition, IL-1β is rapidly sequestered, or secretion, by IL-1Ra and soluble IL-1RI and –RII, once secreted, which makes IL-1β particularly difficult to assay and detect. The biological property of IL-1β underlies the severe phenotype of the rare autoinflammatory disease, deficiency of the interleukin-1–receptor antagonist (DIRA), caused by homozygous mutations in the IL1RN gene, which encoding the IL-1Ra protein (Aksentijevich et al., 2009).

The primary consequence of mutations in the CFTR gene is defective CFTR anion transport and upregulation of Na⁺ transport through dysregulation of ENaC (Muraglia et al., 2019; Peckham et al., 1997). Under in vivo conditions, patients with CF have a more negative baseline airway and nasal potential difference compared to HC and shows an enhanced depolarising response to amiloride, reflecting the inhibition of excessive ENaC mediated Na⁺ influx (Solomon et al., 2018). In airway epithelial cells, increased basolateral Na/K-ATPase activity has also been reported (Peckham et al., 1997). We hypothesised that dysregulation of Na⁺ transport might influence NLRP3 inflammasome activation by increasing K⁺ efflux, a principal trigger for NLRP3 activation (Schorn et al., 2011; Muñoz-Planillo et al., 2013; Katsnelson and George, 2013; Katsnelson et al., 2015; Di et al., 2018; Qu et al., 2017; Zhu et al., 2017; Rivers-Auty and Brough, 2015). We confirmed a dysregulation of Na⁺ and K⁺ transport by examining primary innate immune cells and HBEC lines with CF-associated mutations in vitro and discovered that excessive ENaC-mediated Na⁺ flux, measured indirectly by dependent changes of fluorescence signal, correlate with an increased K⁺ efflux, an activating signal of the NLRP3 inflammasome and downstream IL-18 and IL-1β secretion. We also show that the systemic serum cytokine signature from patients with CF is comparable to patients diagnosed with SAID, characterised by release of proinflammatory IL-1β and IL-18, which are associated with inflammasome activation. On exploration of the inflammation involved, we found a LPS-induced hyper-responsive NLRP3 inflammasome, exclusively in cells with CF-associated mutations, comparable to monocytes from patients with SAID. It should be noted that the SAID patient cohort is comprised of a variety of autoinflammatory diseases that have differing molecular pathophysiology and varying degrees of innate driven inflammation. This NLRP3 inflammasome activation extended beyond IL-18 and IL-1β secretion, with increased propensity for pyroptotic cell death and associated release of NLRP3 inflammasome components, such as ASC, and induction of IFN-γ secretion in the PBMC population. This type of inflammation has similarities to autoinflammation, particularly the IL-1/IL-18 inflammasome signature observed in serum and also present in vitro. The significantly elevated levels of ASC specks in CF sera (Figure 3D), in addition to the proinflammatory IL-1-type cytokine signature (Figure 3A–C), suggests the presence of a NLRP3 inflammasome agonist. A wide range of possible candidates for such an agonist(s) include infectious pathogens (either CF or non-CF related), the patients’ metabolic milieu or, indeed, other unknown agonists. Further work will be necessary to decipher the complex molecular mechanisms involved. This study does not suggest that inflammation is independent of infections in individuals with CF but that the response to said infections is intrinsically dysregulated and predisposed to excessive and inappropriate degrees of inflammation.

Cystic fibrosis is a monogenic disease, yet consists of varying degrees of pathology depending on the precise CFTR mutation and the extent to which the encoded CFTR protein is subsequently transcribed, translated, folded within the ER, expressed on the plasma membrane, its stability on the surface and its ability to conduct chloride and bicarbonate. There are well documented examples of different classes of CFTR mutations that fail at each one of the above stages of CFTR expression and function. The IB3-1 (ΔF508/W1282X) cell line is associated with the greatest amounts of inflammation. The W1282X mutation is associated with severe disease clinically, that can be attributed to little to no protein expression. Inflammation in the IB3-1 cell line in vitro does not correlate with ENaC protein expression. The underlying mechanism of an ENaC/NLRP3 axis driving inflammation in cells with CF-associated mutations may not be common to all mutation classes. Notably, all of the cells (monocytes and epithelia) had at least one ΔF508 allele. Whether the loss of control of ENaC expression and function observed in ΔF508 CFTR expressing cells is unique to this more common mutation will require further study. It is important to note that inhibition of ENaC alleviated NLRP3 inflammasome-mediated inflammation in all cell lines (Figure 5E–F). While inflammation in CF is believed to be driven predominantly by infection, many CFTR mutant animal models have shown that airway inflammation and bronchiectasis can occur under sterile conditions (Montgomery et al., 2017; Keiser et al., 2015; Rao and Grigg, 2006). For instance, in a CFTR knockout ferret model, inflammation, bronchiectasis and mucus accumulation can develop in the absence of infection (Rosenow, 2018). A recent study from the Australian Respiratory Early Surveillance Team for CF highlights the association between pulmonary inflammation and structural lung disease in young children with and without infection (Rosenow et al., 2019). IL-1β is detectable in bronchoalveolar lavage (BAL) fluid from children with CF and is strongly correlated with neutrophil counts, independent from detectable infection (Montgomery et al., 2018). The increased IL-1β neutrophil production in BAL fluid from patients with CF appears to be driven via NLRP3 (McElvaney et al., 2018).

Autoinflammation is defined as an exaggerated inflammatory response, driven by dysregulated innate immune cells, in the absene of antigen-driven T-cells, B-cells, or associated autoantibodies (Peckham et al., 2017; McDermott et al., 1999; McDermott and Aksentijevich, 2002; McGonagle and McDermott, 2006; Stoffels and Kastner, 2016). Adaptive immune cells may be recruited in response to the downstream consequences of autoinflammation, with increased susceptibility to infection, and progression to autoimmunity and hyperinflammation (Wekell et al., 2016). In fact, we have shown that endoplasmic reticulum (ER) stress present in CF innate immune cells, including neutrophils, monocytes and M1 macrophages, causes an exaggerated inflammatory response (Lara-Reyna et al., 2019). Based on these data and cited literature, CF displays features of autoinflammatory disease, in part driven by aberrant ionic fluxes and recurrent infections. The NLRP3 inflammasome can be primed by proinflammatory cytokines, such as TNF, although bacterial components do provide a far more potent stimulus (Swanson et al., 2019; McElvaney et al., 2019).

Targeting the exaggerated inflammatory response without simultaneously predisposing individuals to infection remains an elusive goal which carries inherent (potential) risk. This was highlighted by the termination of a study investigating a leukotriene B_4- (LTB₄) receptor antagonist for treatment of lung disease in CF following a disproportionate incidence of respiratory serious adverse events (Konstan et al., 2014). Treating inflammation remains a priority and multiple trials targeting various anti-inflammatory pathways are ongoing (Cystic Fibrosis Foundation, 2017). There is evidence in the literature of endotoxin tolerant monocytes from patients with CF, with reduced cytokine expression in response to repetitive endotoxin exposure (del Campo et al., 2011; del Fresno et al., 2009; del Fresno et al., 2008). However, we propose that peripheral monocytes such as those used in this study, are not constantly exposed to common pathogenic antigens that exist within the lung microenvironment during infections. In fact, one may propose a scenario of trained immunity, where innate immune cells hyper-respond to the recurrent infections with greater destructive consequences. Endotoxins are not the only inflammatory stimulus for NLRP3 inflammasome priming that exist in the inflammatory milieu of the CF lung. Epithelial derived cytokines, neutrophilic extracellular traps (NETs), necrotic cell death and subsequent damage associated molecular patterens (DAMPs) may all induce transcription of IL-1β/IL-18 and other inflammasome components, independent of endotoxins. A caveat of our study is that we have not tested the full array of DAMPs and pathogen associated molecular patterns (PAMPs) that exist in the CF lung that may trigger the intrinsic predisposition to NLRP3 inflammasome activation observed in this study.

The data here suggest that IL-18 may be a useful therapeutic target, by preventing adaptive cell airway infiltration whilst maintaining a potent IL-1β response to infection (Gabay et al., 2018); however, NLRP3 activation exercises a protective role in animal models of induced colitis (Allen et al., 2010), running contrary to the expectation that reduced NLRP3 expression might reduce inflammation in the bowel. Furthermore, IL-18 has an epithelial protective role in promoting repair of gut epithelium (Zaki et al., 2010), and more ex vivo studies and CF disease models are required to elucidate the benefits or hazards of IL-18 blockade. Anakinra is a viable therapeutic option for CF, particularly with its short half-life and daily treatment regime allowing a more controlled dosage during any inevitable infections. In fact a phase IIa clinical trial to evaluate safety and efficacy of subcutanous administration of anakinra in patients with cystic fibrosis is in progress (EudraCT Number: 2016-004786-80). It is notable that inhibition of TLR4 signalling was the most effective means of blocking NLRP3 activation in our study, which suggests that targeting this pathway may be a therapeutic option in CF (Keeler et al., 2019; Greene et al., 2008). These novel data, along with our observation that decreased intracellular K⁺ levels upon stimulation with ATP in cells with CF-associated mutations, correlates with the characteristic and excessive ENaC-mediated Na⁺ transport, suggest that CF-associated mutations lower the threshold for NLRP3 assembly, rather than priming this key intracellular component of innate immune defenses.

Through inhibition of amiloride-sensitive Na⁺ channels, we were able to reduce NLRP3 inflammasome activation, and associated IL-18 and IL-1β secretion, in vitro. Notably, ENaC inhibition did not modulate IL-18 and IL-1β secretion in monocytes from individuals with SAID, indicating the proposed ENaC-NLRP3 axis is unique to CF-associated mutations. These findings highlight the importance of excessive ENaC-mediated intracellular Na⁺ as a disease mechanism in CF, and also highlight its potential as a therapeutic target. Targeting amiloride-sensitive Na⁺ channels such as ENaC to restoring airway surface liquid and mucociliary clearance, has been previously attempted, using amiloride in the 1990 s, with little efficacy, due to amiloride’s short half-life and limited effectiveness (Graham et al., 1993).

In conclusion, we have shown that hypersensitive NLRP3 inflammasome activation in CF induces proinflammatory serum and cellular profiles. Overexpression of β-ENaC, in the absence of CFTR dysfunction as well as dysregulation of amiloride-sensitive Na⁺ channel activity in CF, further potentiates LPS-induced NLRP3 inflammasome activity. Both ENaC and NLRP3 are potential therapeutic targets for reducing inflammation in patients with CF.

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

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Author details

1. Thomas Scambler

   Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Heledd H Jarosz-Griffiths

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2468-0218

2. Heledd H Jarosz-Griffiths

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

   Contribution

   Data curation, Formal analysis, Investigation, 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

3. Samuel Lara-Reyna

   1. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
   2. Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

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

4. Shelly Pathak

   Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

5. Chi Wong

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

   Contribution

   Data curation, Formal analysis, Project administration

   Competing interests

   No competing interests declared

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

6. Jonathan Holbrook

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

   Contribution

   Writing—review and editing

   Competing interests

   No competing interests declared

7. Fabio Martinon

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

   Contribution

   Conceptualization, Supervision, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

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

8. Sinisa Savic

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

   Contribution

   Conceptualization, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

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

9. Daniel Peckham

   1. Leeds Institute of Medical Research, 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’ University Hospital, Leeds, United Kingdom

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Visualization, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Michael F McDermott

   Competing interests

   No competing interests declared

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

10. Michael F McDermott

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

    Contribution

    Conceptualization, Resources, Funding acquisition, Investigation, Writing—original draft, Project administration, Writing—review and editing

    Contributed equally with

    Daniel Peckham

    For correspondence

    M.McDermott@leeds.ac.uk

    Competing interests

    No competing interests declared

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

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