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Inflammasomes in Respiratory DiseaseInflammasomes in Lung Disease: From Bench to Bedside FREE TO VIEW

Guy G. Brusselle, MD, PhD; Sharen Provoost, PhD; Ken R. Bracke, PhD; Anna Kuchmiy, PhD; Mohamed Lamkanfi, PhD
Author and Funding Information

From the Laboratory for Translational Research of Obstructive Pulmonary Disease (Drs Brusselle, Provoost, and Bracke), Ghent University Hospital, Ghent, Belgium; the Departments of Epidemiology and Respiratory Medicine (Dr Brusselle), Erasmus MC, Rotterdam, The Netherlands; the Department of Medical Protein Research (Drs Kuchmiy and Lamkanfi), Flanders Institute for Biotechnology (VIB), Ghent, Belgium; and the Department of Biochemistry (Drs Kuchmiy and Lamkanfi), Ghent University, Ghent, Belgium.

Correspondence to: Guy G. Brusselle, MD, PhD, Laboratory for Translational Research of Obstructive Pulmonary Disease, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium; e-mail: guy.brusselle@ugent.be


Funding/Support: Work in Dr Lamkanfi’s laboratory is supported in part by the European Union [Marie-Curie Grant 256432], European Research Council [Grant 281600], and the Fund for Scientific Research Flanders (FWO) [Grants G030212N, 1.2.201.10.N.00, and 1.5.122.11.N.00]. Drs Provoost and Bracke are postdoctoral researchers of FWO. Presented work within the Department of Respiratory Medicine of Ghent University is funded by grants from the FWO, the Concerted Action of Ghent University, and the Interuniversity Attraction Poles Program.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(5):1121-1133. doi:10.1378/chest.13-1885
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The respiratory tract of human subjects is constantly exposed to harmful microbes and air pollutants. The immune system responds to these offenders to protect the host, but an unbalanced inflammatory response itself may promote tissue damage and ultimately lead to acute and chronic respiratory diseases. Deregulated inflammasome activation is emerging as a key modulator of respiratory infections and pathologic airway inflammation in patients with asthma, COPD, and pulmonary fibrosis. Assembly of these intracellular danger sensors in cells of the respiratory mucosa and alveolar compartment triggers a proinflammatory cell death mode termed pyroptosis and leads to secretion of bioactive IL-1β and IL-18. Here, we summarize and review the inflammasome and its downstream effectors as therapeutic targets for the treatment of respiratory diseases.

Figures in this Article

Acute and chronic respiratory diseases represent major threats to human health. In this regard, a large-scale assessment of global disease burden identified tobacco smoking and air pollution as two of the top three risk factors threatening global human health.1 In normal homeostatic conditions, the respiratory mucosa, dendritic cells, and alveolar macrophages maintain a delicate balance by responding in an appropriate and timely manner to pathogenic microbes and air pollutants. Deficient mucosal inflammatory and immune responses to microorganisms may lead to lower respiratory tract infections and pneumonia. In contrast, exaggerated or persistent responses of the bronchial and alveolar epithelium to environmental exposures may contribute to the pathogenesis of diverse pulmonary diseases, such as acute lung injury, pulmonary fibrosis, asthma, and COPD. Alveolar macrophages, dendritic cells, and bronchial epithelial cells are equipped with so-called “pattern recognition receptors” (PRRs) that detect and respond to exogenous and endogenous stress signals. PRR protein families include members of the Toll-like receptor (TLR), C-type lectin receptor, nucleotide-binding oligomerization domain-like receptor (NLR), retinoic acid-inducible gene-I-like receptor, and absent in melanoma 2 (AIM2)-like receptor (ALR) protein families. Engagement of these PRRs initiates a complex series of inflammatory signaling cascades that guide the host’s immune responses to eliminate microbial and nonmicrobial threats. In addition, these receptors steer the subsequent tissue repair phase. The biology of distinct PRR families is discussed in depth elsewhere.2,3 In the following sections, we briefly introduce NLRs and ALRs in the context of inflammasome signaling, followed by an overview of our current understanding of the pathologic role and therapeutic potential of these protein complexes in respiratory infections and acute or chronic inflammatory lung diseases.

Inflammasomes: Platforms for Caspase-1 Activation

Inflammasomes are defined as intracellular multiprotein complexes that facilitate the proximity-induced autoactivation of the proinflammatory cysteine protease caspase-1. Similar to apical caspases activating the death receptor-mediated and the mitochondria-dependent apoptotic cell death pathways, caspase-1 is produced as an inactive protease zymogen that resides in the cytosol of myeloid and epithelial cells. Upon detection of endogenous or exogenous signals indicating imminent danger, sensor proteins of the NLR and ALR protein families oligomerize and recruit caspase-1 zymogens into the complex. Conformational changes in caspase-1 zymogens that are recruited to the inflammasome—along with the high local concentrations of the zymogen in the complex—lock the protease in an enzymatically active state. Active caspase-1 subsequently cleaves IL-1β and IL-18, an event essential for extracellular secretion of the bioactive forms of these major proinflammatory cytokines.4

IL-1β is a pleiotropic proinflammatory cytokine expressed mainly by innate immune cells, which promotes both local and systemic inflammatory responses by inducing fever, recruiting additional innate immune cells, and activating lymphocytes. Moreover, IL-1β participates in the induction of adaptive T helper (Th) 1, Th17, and humoral responses during infection.5 On the other hand, some evidence suggests a deleterious role for excessive IL-1β production in chronic inflammatory pulmonary diseases, such as COPD, asthma, pulmonary fibrosis, and pneumoconiosis.6,7 Myeloid and pulmonary epithelial cells also express IL-18. This cytokine lacks the pyrogenic activity of IL-1β but plays an important role in T-cell polarization by skewing T-cell responses toward either a Th1 or Th2 profile, depending on the inflammatory context. IL-18 also promotes IL-17 expression by already-committed Th17 cells.8,9

Unlike most cytokines, IL-1β and IL-18 are not released through the classic endoplasmic reticulum-Golgi route but are produced as cytosolic precursor proteins waiting for their maturation by caspase-1. Other cytokines, chemokines, and growth factors that may rely on the inflammasome for their secretion include IL-1α, high mobility group box 1, and fibroblast growth factor 2.10 IL-1β, IL-18, and the latter proteins are sometimes referred to as “danger signals” or “alarmins,” as their release may be accompanied by programmed necrosis or pyroptosis, two incompletely characterized proinflammatory cell death modes. Whereas programmed necrosis relies on the kinases receptor interacting protein 1 and receptor interacting protein 3, pyroptotic cell death requires activity of the inflammatory caspases 1 and/or 11.11,12 Pyroptosis is emerging as a new mechanism by which inflammasomes contribute to host defense responses against microbial pathogens in the respiratory and intestinal tracts. Pyroptosis halts intracellular pathogen replication by eliminating infected immune cells and may at the same time boost innate and adaptive immune responses by releasing the infectious agent and alarmins into the extracellular milieu.4 However, progress in understanding the in vivo roles of pyroptosis is hampered by the absence of specific markers and limited insight in the molecular mechanisms of this programmed cell death mode.

Inflammasome Subtypes

Inflammasomes typically are named after the platform protein of the NLR or ALR family that acts as scaffold for caspase-1 recruitment. At least four distinct inflammasome complexes (namely the NLR, pyrin domain-containing 1b [NLRP1b]; NLR, pyrin domain-containing 3 [NLRP3]; NLR, caspase activation and recruitment domain-containing 4 [NLRC4]; and AIM2 inflammasomes) that activate caspase-1 in response to specific microbial infections and stress conditions were validated in knockout mice, and several more putative complexes are under study. Although the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) is required for assembly of the NLRP3 and AIM2 complexes, it has a more confined role in the NLRC4 and NLRP1b inflammasomes (Fig 1). A study showed that ASC is critical for caspase-1 autoproteolysis and cytokine maturation but dispensable for induction of pyroptotic cell death by the NLRC4 inflammasome.13

Figure Jump LinkFigure 1. Overview of inflammasome composition and activating stimuli. Four inflammasome platforms are described: neucleotide-binding oligomerization domain-like receptor (NLR) family members mouse NLRP1b/human NLRP1, NLRP3, and NLRC4, and the PYHIN family member AIM2. NLR family members typically contain carboxy-terminal LRRs that are involved in ligand sensing, a central NACHT, and an amino-terminal CARD or a PYD that mediates protein-protein reactions for downstream signaling. AIM2 contains a carboxy-terminal HIN200 domain implicated in ligand sensing and an amino-terminal PYD. Once activated, the inflammasome platforms oligomerize and recruit caspase-1, either directly through homotypic CARD-CARD interactions, or indirectly through the adaptor ASC. Please refer to Table 1 for PAMPs activating NLRP3. DAMPs activating NLRP3 include adenosine-5′-triphosphate (ATP), uric acid crystals, amyloid-β fibrils, and hyaluronan. AIM2 = absent in melanoma 2; ASC = apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; B. anthracis = Bacillus anthracis; CARD = caspase activation and recruitment domain; DAMP = damage-associated molecular pattern; FIIND = domain with function to find; F. tularensis = Francisella tularensis; K. pneumoniae = Klebsiella pneumoniae; L. pneumophila = Legionella pneumophila; LRR = leucine rich repeat; M. tuberculosis = Mycobacterium tuberculosis; NACHT = nucleotide-binding and oligomerization domain; NLRC4 = nucleotide-binding oligomerization domain-like receptor, caspase activation and recruitment domain-containing 4; NLRP1b = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 1b; NLRP3 = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3; P. aeruginosa = Pseudomonas aeruginosa; PAMP = pathogen-associated molecular pattern; PYD = pyrin domain; PYHIN = pyrin and HIN200 (hematopoietic interferon-inducible nuclear antigens with 200 amino-acid repeats) domain-containing protein.Grahic Jump Location

Significant progress was made in understanding the activation mechanisms of inflammasomes in recent years. The only currently known trigger for the NLRP1b inflammasome is lethal toxin of Bacillus anthracis, the causative agent of anthrax. NLRP1b inflammasome-induced cytokine production and pyroptosis were shown to cause acute lung injury and morbidity in mice that were intratracheally dosed with anthrax lethal toxin.14 Unlike NLRP1b, the NLRP3 inflammasome responds to a broad spectrum of infectious agents, foreign particulate matter, and endogenous molecules associated with tissue damage and stress. In respect to pulmonary infections, myeloid cells respond with NLRP3 inflammasome activation upon infection with the bacterial pathogens Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Chlamydia pneumoniae, and Mycobacterium tuberculosis (Table 1).15-41 In addition, the fungal pathogens Candida albicans and Aspergillus fumigatus and the viral pathogens influenza A and respiratory syncytial virus are detected by the NLRP3 inflammasome (Table 1). Moreover, alarmins such as adenosine-5′-triphosphate (ATP), uric acid crystals, amyloid-β fibrils, and hyaluronan that often are produced or released under conditions of noninfectious pulmonary inflammation all activate NLRP3 as well.4 Crystalline substances such as alum, silica, and asbestos mimic microbial toxins and lead to NLRP3 activation by inducing K+ efflux.42

Table Graphic Jump Location
Table 1 —Activation of Inflammasomes by Respiratory Pathogens

The inflammasome-activating microbial components and the relevant inflammasomes are listed. AIM2 = absent in melanoma 2; CyaA = adenylate cyclase; ESAT-6 = 6kDa early secreted antigenic target; NLRC4 = nucleotide-binding oligomerization domain-like receptor, caspase activation and recruitment domain-containing 4; NLRP1b = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 1b; NLRP3 = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3; NLRP7 = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 7.

The scope of molecular agonists of the NLRC4 inflammasome is more limited and to date mainly comprises flagellin and bacterial secretion systems.43 As such, this inflammasome responds to bacterial infections with Pseudomonas aeruginosa (eg, in patients with cystic fibrosis or non-cystic fibrosis bronchiectasis) and Legionella pneumophila (Legionnaires’ disease). The AIM2 inflammasome activates caspase-1 when the host is infected by Francisella tularensis, which may cause potentially lethal pneumonic tularemia when bacteria are inhaled.44 In addition, the AIM2 inflammasome responds to DNA viruses (Table 1). The interested reader is referred to other reviews discussing inflammasome composition and activation mechanisms in additional depth.4,44 In the following paragraphs, we focus on detailing the pathophysiologic roles of the NLRP3, NLRC4, and AIM2 inflammasomes in respiratory infections and inflammatory lung diseases.

Flu (Influenza A Virus)

Influenza A virus, a negative-stranded RNA virus, is a major cause of human respiratory infections and a frequent trigger of exacerbations in patients with asthma or COPD. Influenza A viruses are sensed by three different PRRs, namely the endosomal TLR7 that recognizes viral single-stranded RNA (ssRNA), the cytosolic retinoic acid-inducible gene-I receptor that senses viral ssRNA bearing 5′-triphosphates, and the NLRP3 inflammasome that activates caspase-1 in macrophages and dendritic cells.45 Intriguingly, influenza A virus provides both signals 1 and 2 for activation of the NLRP3 inflammasome (Fig 2). Sensing of influenza ssRNA by TLR7 in endosomes activates the transcription factor nuclear factor-κB to induce transcriptional upregulation of NLRP3 and the precursor forms of the inflammasome-dependent cytokines proIL-1β and proIL-18.45 Next, the influenza virus M2 protein, a proton-selective ion channel, triggers assembly and activation of the NLRP3 inflammasome, possibly by perturbing intracellular ionic concentrations.37

Figure Jump LinkFigure 2. Two signals are needed to activate the NLRP3 inflammasome. Although the exact molecular mechanisms of NLRP3 assembly and subsequent IL-1β maturation remain incompletely understood, it is well established that at least two distinct signals are required. The first signal induces transcription of proIL-1β, proIL-18, and NLRP3 inflammasome. K+ efflux represents the second signal and mediates NLRP3 inflammasome assembly and subsequent caspase-1 activation. Ultimately, caspase-1 processes proIL-1β and proIL-18 into bioactive cytokines and induces pyroptosis. HMGB1 = high mobility group box 1; NF-κB = nuclear factor κB; P2X7 = purinergic receptor; ROS = reactive oxygen species; TLR = Toll-like receptor. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Several reports demonstrated that inflammasome signaling is required for protection against influenza virus infection in experimental murine models.38-40 ASC−/− and caspase-1−/− mice were indeed more susceptible than wild-type mice after infection with a pathogenic influenza virus, and this enhanced morbidity and mortality correlated with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production.38-40 In addition, IL-1β levels in the BAL fluid of NLRP3−/− mice were significantly reduced upon influenza A virus infection, implicating the NLRP3 inflammasome in protection against influenza. In agreement, two research groups found influenza-induced mortality to be significantly increased In NLRP3−/− mice, although induction of adaptive immunity against the virus was not affected.38,40

Pneumonia

Deregulated activation of inflammasomes in the setting of acute bacterial or viral pneumonia might compromise lung function and gas exchange, provoking acute lung injury and ARDS (Table 1).46,47 In response to microbial infections of the respiratory tract, inflammasome activation in epithelial cells and alveolar macrophages leads to production of the proinflammatory cytokines IL-1β and IL-18, which contribute to protection of the host by inducing innate and adaptive immune responses that limit microbial invasion.48 The IL-1β-mediated recruitment of neutrophils to the lungs is required for effective clearance of diverse respiratory pathogens, by a combination of phagocytosis and neutrophil extracellular trap formation. In addition, activation of caspase-1 induces pyroptosis, a lytic form of cell death that restricts replication of intracellular bacteria such as L pneumophila (Table 1).49

In experimental models of pneumonia, ASC−/− mice were more susceptible than wild-type mice to intranasal infection with S pneumoniae, with impaired secretion of IL-1β and IL-18 into the BAL fluid.27 Human mononuclear cells respond to S pneumoniae expressing hemolytic pneumolysin by producing IL-1β via activation of the NLRP3 inflammasome. Interestingly, the inflammasome pathway is not activated by serotypes of S pneumoniae producing toxins with reduced hemolytic activity and causing invasive disease.28 Upon infection with S aureus, IL-1β plays an essential role in the differentiation of naive T cells toward Th17 cells, which coordinate adaptive immunity toward extracellular bacteria.50 Together, these observations suggest inflammasome activation as a critical component of the host’s immune and defense mechanisms that aids in fighting pneumonia and clearing respiratory infections.

TB (M tuberculosis)

Recognition of M tuberculosis by the host occurs via several classes of pattern recognition receptors, including membrane-bound TLRs (including TLR2, TLR4, and TLR9) and C-type lectin receptors, and the cytoplasmic sensors nucleotide-binding oligomerization domain 2, NLRP3, and AIM2.51,52 The M tuberculosis virulence factor 6kDa early secreted antigenic target, implicated in membrane damage, is a potent activator of the NLRP3 inflammasome in macrophages.32 However, NLRP3 deficiency did not predispose to increased susceptibility to M tuberculosis since NLRP3−/− mice controlled experimental pulmonary TB, implicating an NLRP3-independent production of IL-1β/IL-18 and induction of protective immunity in infected lungs.53,54 In this regard, AIM2, which senses cytosolic DNA of M tuberculosis, has been shown to mediate M tuberculosis-induced inflammasome activation, leading to IL-1β and IL-18 production and protective Th1 responses; AIM2−/− mice, therefore, appeared highly susceptible to M tuberculosis infection.33

Adaptive Th1 immune responses, producing interferon-γ and IL-18, are effective in protection against the intracellular pathogen M tuberculosis. Intriguingly, interferon-γ suppresses excessive M tuberculosis-induced immunopathology by triggering inducible nitric oxide synthase; the resulting nitric oxide specifically inhibits the assembly of the NLRP3 inflammasome via thio-nitrosylation of NLRP3.55 Whereas IL-1β is an important mediator of innate immunity in acute respiratory infections, it can promote inflammatory tissue damage during chronic infections such as TB. Therefore, failure to turn off the inflammasome might contribute to lung pathology in chronic TB disease.

Asthma

A common denominator of chronic inflammatory lung diseases, such as asthma, COPD, and pulmonary fibrosis, is that they represent complex diseases that result from the interaction between genetic susceptibility and environmental exposures. Indeed, several findings suggest that the inflammasome pathway might be involved in the pathogenesis of asthma. First, genomewide association studies of asthma have shown a significant association with single-nucleotide polymorphisms within the IL18R1 gene on chromosome 2q21.56 Moreover, functional NLRP3 polymorphisms, which increase the stability of NLRP3 messenger RNA and NLRP3 expression, have been associated with aspirin-induced asthma.57 Second, in an adjuvant-free experimental model of allergic asthma induced by ovalbumin (OVA), allergic airway inflammation depended on NLRP3 inflammasome activation, leading to IL-1β production and the induction of a Th2 inflammatory response.58 Indeed, OVA-induced airway hyperresponsiveness was significantly decreased in IL-1β knockout mice.59 However, the role of the NLRP3 inflammasome in the pathogenesis of allergic airway disease in mice is controversial, as Allen et al60 did not find significant differences in airway eosinophilia, mucus production, or airway hyperresponsiveness between wild-type and NLRP3−/− mice in acute (alum-dependent) and chronic (alum-independent) OVA models. In addition, they did not detect a role for NLRP3 in the development of allergic airway disease induced by acute or chronic exposure to house dust mite allergens.60

Although the role of the NLRP3 inflammasome in stable allergic asthma is debated, it might be involved in other phenotypes of asthma (eg, nonallergic eosinophilic and neutrophilic asthma) or during exacerbations of the disease, which are most frequently provoked by respiratory infections (see previous) or air pollution.61 Using in vitro studies on human airway epithelial cells and in vivo studies in NLRP3−/− and wild-type mice, Hirota et al62 elegantly demonstrated that NLRP3 expressed in the airway epithelium is activated by urban particulate matter, leading to caspase-1 cleavage and production of IL-1β.

COPD

It is tempting to speculate that the NLRP3 inflammasome is involved in the pathogenesis of the chronic airway inflammation in COPD, since increased levels of several activators of NLRP3 are present in the airways and lungs of patients with COPD, encompassing extracellular ATP, uric acid (crystals), reactive oxygen species, and bacterial pathogen-associated molecular patterns.63,64 Extracellular ATP activates the NLRP3 inflammasome by engaging the purinergic receptor (P2X7), whereas crystals and particulate matter induce K+ efflux independently of P2X7 consequent to lysosomal damage.42,65

Increased activation of caspase-1 has been observed in lung tissue from patients with severe COPD and smoking donors compared with nonsmoking donors.66 Also, the downstream effector molecules of the NLRP3 inflammasome pathway, IL-1β and IL-18, are increased in patients with COPD.67-69 Elevated protein levels of IL-1β have been shown in induced sputum and in lung biopsies of patients with mild to moderate COPD.67,68 Moreover, sputum levels of IL-1α and IL-1β were further increased during COPD exacerbations compared with levels measured during the stable state.68 In addition, increased production of IL-18 by alveolar macrophages, CD8+ T cells, and bronchial and alveolar epithelial cells has been demonstrated in the lungs of patients with COPD.69

In this regard, cigarette smoke (CS)-induced neutrophilia in mice was associated with increased caspase-1 activity and downstream markers of inflammasome activation (mature IL-1β and IL-18).66 Notably, IL-1R−/− mice were protected not only against acute CS-mediated increases in BAL inflammatory cells and matrix breakdown but also against chronic CS-induced emphysema.70 However, the acute CS-induced pulmonary inflammation was not significantly attenuated in NLRP3−/− and caspase-1−/− mice compared with wild-type control mice, suggesting that also IL-1α contributed to IL-1R-mediated inflammation upon CS exposure.67,68 Chronic CS experiments and mouse models combining CS exposure with respiratory infections, attempting to mimic COPD exacerbations, are warranted to fully elucidate the functional role of the NLRP3 (and other) inflammasomes in vivo.

Pulmonary Fibrosis (Asbestosis, Silicosis, and Idiopathic Pulmonary Fibrosis)

Several lines of evidence suggest that inflammasomes, and particularly the NLRP3 inflammasome, might be involved in the pathogenesis of fibrosing lung diseases, including idiopathic pulmonary fibrosis and diseases elicited by known environmental exposures (eg, asbestosis and silicosis). Single nucleotide polymorphisms in the NLRP3 gene have been associated with coal worker pneumoconiosis, which results from the inhalation of silica-containing coal mine dust and eventually develops into progressive pulmonary fibrosis.71 In vitro studies have demonstrated that asbestos and silica are sensed by the NLRP3 inflammasome, whose subsequent activation leads to secretion of active IL-1β.72,73 Activation of NLRP3 by silica required phagocytosis of silica crystals by macrophages, which subsequently led to lysosomal damage and rupture.72 Although generation of reactive oxygen species, and increased levels of intracellular calcium, sensed by the calcium-sensing receptor, were believed to be involved in the activation of the NLRP3 inflammasome by asbestos or silica,74,75 a recent report showed that efflux of intracellular potassium was required and sufficient for NLRP3 activation.42 In mouse models of asbestosis and silicosis, NLRP3−/− mice showed decreased numbers of inflammatory cells in the lungs and lower cytokine production upon exposure to inhaled asbestos or silica, compared with control littermates.73,75 Importantly, 3 months after silica challenge, NLRP3−/− mice had less collagen deposition on trichrome staining in lung sections than wild-type mice. Whether the NLRP3 inflammasome is mainly required for the early phases in the development of pulmonary fibrosis or is also involved in the progression of established disease needs to be elucidated. Addressing this issue will be important in resolving the potential effectiveness of inflammasome inhibition in a therapeutic setting.

The inflammasome provides several promising targets for pharmacological intervention in respiratory infection and chronic lung inflammation. Modulation of inflammasome-dependent biologic outcomes may be accomplished at several levels, for instance by preventing the nuclear factor-κB-dependent upregulation of NLRP3 and the inflammasome substrates proIL-1β and proIL-18 (eg, BAY 11-7082); by inhibiting inflammasome assembly and activation by means of P2X7 antagonists, glyburide, or cytokine release inhibitory drug 3 molecules; by directly inhibiting caspase-1 enzymatic activity; or by blocking secreted IL-1β/IL-18 and their cognate receptors (Fig 3). Molecules currently approved for use in the clinic and those in diverse phases of clinical investigation particularly focus on neutralizing IL-1β and IL-18 (Table 2).76-84 The IL-1β neutralizing antibody canakinumab displayed mild efficacy in attenuating the late asthmatic response after inhalative allergen challenge and pulmonary function in phase 1/2 trials for asthma and COPD, respectively.85 It remains to be seen whether drugs that are currently being tested in COPD, such as MEDI8968, a blocking antibody targeting the IL-1 receptor, and the human anti-IL-18 monoclonal antibody MEDI2338, will prove more efficacious (Table 2). In addition, IL-1β-targeting agents such as anakinra, rilonacept, gevokizumab, LY2189102, AMG108, CYT-013, and EBI-005 that currently are in phase 1/2 testing for inflammatory diseases in other tissues also could be worthwhile exploring for the treatment of chronic respiratory inflammatory disorders.86

Figure Jump LinkFigure 3. A schematic overview of potential therapeutic targets in the inflammasome and IL-1/18 pathways. The inflammasome pathway provides several promising targets for pharmacologic intervention in respiratory infection and chronic lung inflammation. Interfering with inflammasome signaling may be accomplished by preventing NF-κB-dependent upregulation of proIL-1β, proIL-18, and NLRP3 (eg, BAY 11-7082); by inhibiting its assembly and activation upstream in the pathway (eg, P2X7 antagonists, glyburide, and CRID3 molecules); by inhibiting caspase-1 enzymatic activity; or by blocking secreted IL-1β/IL-18 and their cognate receptors in autocrine/paracrine ways. CRID3 = cytokine release inhibitory drug 3; mAb = monoclonal antibody. See Figure 1 and 2 legends for expansion of other abbreviationsGrahic Jump Location
Table Graphic Jump Location
Table 2 —Pharmacologic Targeting of the Inflammasome Pathway in Respiratory Diseases

CAPS = cryopyrin-associated periodic syndrome; FDA = US Food and Drug Administration; FEF25%-75% = forced expiratory flow between 25% and 75%; LAR = late asthmatic response; PD20 = provocative dose causing a 20% fall in FEV1; RA = rheumatoid arthritis; Refs = references; SVC = slow vital capacity.

New therapeutic strategies targeting inflammasome signaling upstream in the signaling cascade might prove more effective than single cytokine therapies, as they would simultaneously neutralize IL-1β and IL-18 secretion by preventing inflammasome-induced caspase-1 activation. Potential agents that could be explored in this direction for the treatment of chronic lung inflammation include the small molecule inflammatory caspase inhibitor VX-765, which is currently in phase 2 testing for treatment-resistant epilepsy, and the P2X7 receptor antagonists AZD9056, CE-224,535, and GSK1482160.87,88 The P2X7 receptor blocker AZD9056 was well tolerated but failed to show disease improvement in patients with COPD89 (Table 2). This is perhaps not surprising, as activation of the NLRP3 inflammasome by all stimuli but ATP proceeds unhampered in the absence of the P2X7 receptor.90 Regardless, one should keep in mind the key importance of inflammasomes in host defense against respiratory infections when exploring experimental therapies aimed at chronically inhibiting inflammasomes. Indeed, patients with COPD and asthma often suffer from respiratory tract infections, indicating that caution should be exercised when blocking inflammasome activation in such patients.91

Although currently available information on the risk profiles of antiinflammasome therapies in the context of chronic respiratory disease is limited (Table 2), anakinra, canakinumab, and rilonacept displayed a remarkable safety record in patients with cryopyrin-associated periodic syndromes and rheumatoid arthritis. Controlled trials for these indications mainly revealed an increased occurrence of viral upper airway infections relative to placebo control subjects. Moreover, bacterial infections with organisms such as S pneumoniae and S aureus are of concern in patients receiving anti-IL1 therapy.86 However, the lack of opportunistic infections such as TB, histoplasmosis, listeriosis, and aspergillosis distinguishes IL-1-based therapeutics from other biologic agents such as tumor necrosis factor blockers.92-94 Finally, because selective IL-1β blockers have a different mechanism of action compared with anakinra, canakinumab, and rilonacept (which block both IL-1β and IL-1α signaling), the long-term safety and efficacy profiles of these drugs may differ significantly from existing anti-IL-1 therapies. Consequently, additional evaluation is needed to assess the safety and efficacy of anti-inflammasome therapies in the context of chronic respiratory diseases.

In conclusion, the inflammasome is a promising target for pharmacologic intervention in respiratory infection and chronic lung inflammation. Treatment of respiratory infections may benefit from inflammasome activation in the context of vaccination strategies against pulmonary infections (eg, influenza virus A vaccines). On the other hand, lung-specific and inflammasome-selective inhibition may appear more appropriate for treating chronic inflammatory disorders such as asthma and COPD.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: There was no role for the funding bodies in writing and editing of the manuscript.

AIM2

absent in melanoma 2

ALR

absent in melanoma 2-like receptor

ASC

apoptosis-associated speck-like protein containing a caspase activation and recruitment domain

ATP

adenosine-5′-triphosphate

CS

cigarette smoke

NLR

nucleotide-binding oligomerization domain-like receptor

NLRC4

nucleotide-binding oligomerization domain-like receptor, caspase activation and recruitment domain-containing 4

NLRP1b

nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 1b

NLRP3

nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3

OVA

ovalbumin

P2X7

purinergic receptor

PRR

pattern recognition receptor

ssRNA

single-stranded RNA

Th

T helper

TLR

Toll-like receptor

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Figures

Figure Jump LinkFigure 1. Overview of inflammasome composition and activating stimuli. Four inflammasome platforms are described: neucleotide-binding oligomerization domain-like receptor (NLR) family members mouse NLRP1b/human NLRP1, NLRP3, and NLRC4, and the PYHIN family member AIM2. NLR family members typically contain carboxy-terminal LRRs that are involved in ligand sensing, a central NACHT, and an amino-terminal CARD or a PYD that mediates protein-protein reactions for downstream signaling. AIM2 contains a carboxy-terminal HIN200 domain implicated in ligand sensing and an amino-terminal PYD. Once activated, the inflammasome platforms oligomerize and recruit caspase-1, either directly through homotypic CARD-CARD interactions, or indirectly through the adaptor ASC. Please refer to Table 1 for PAMPs activating NLRP3. DAMPs activating NLRP3 include adenosine-5′-triphosphate (ATP), uric acid crystals, amyloid-β fibrils, and hyaluronan. AIM2 = absent in melanoma 2; ASC = apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; B. anthracis = Bacillus anthracis; CARD = caspase activation and recruitment domain; DAMP = damage-associated molecular pattern; FIIND = domain with function to find; F. tularensis = Francisella tularensis; K. pneumoniae = Klebsiella pneumoniae; L. pneumophila = Legionella pneumophila; LRR = leucine rich repeat; M. tuberculosis = Mycobacterium tuberculosis; NACHT = nucleotide-binding and oligomerization domain; NLRC4 = nucleotide-binding oligomerization domain-like receptor, caspase activation and recruitment domain-containing 4; NLRP1b = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 1b; NLRP3 = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3; P. aeruginosa = Pseudomonas aeruginosa; PAMP = pathogen-associated molecular pattern; PYD = pyrin domain; PYHIN = pyrin and HIN200 (hematopoietic interferon-inducible nuclear antigens with 200 amino-acid repeats) domain-containing protein.Grahic Jump Location
Figure Jump LinkFigure 2. Two signals are needed to activate the NLRP3 inflammasome. Although the exact molecular mechanisms of NLRP3 assembly and subsequent IL-1β maturation remain incompletely understood, it is well established that at least two distinct signals are required. The first signal induces transcription of proIL-1β, proIL-18, and NLRP3 inflammasome. K+ efflux represents the second signal and mediates NLRP3 inflammasome assembly and subsequent caspase-1 activation. Ultimately, caspase-1 processes proIL-1β and proIL-18 into bioactive cytokines and induces pyroptosis. HMGB1 = high mobility group box 1; NF-κB = nuclear factor κB; P2X7 = purinergic receptor; ROS = reactive oxygen species; TLR = Toll-like receptor. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. A schematic overview of potential therapeutic targets in the inflammasome and IL-1/18 pathways. The inflammasome pathway provides several promising targets for pharmacologic intervention in respiratory infection and chronic lung inflammation. Interfering with inflammasome signaling may be accomplished by preventing NF-κB-dependent upregulation of proIL-1β, proIL-18, and NLRP3 (eg, BAY 11-7082); by inhibiting its assembly and activation upstream in the pathway (eg, P2X7 antagonists, glyburide, and CRID3 molecules); by inhibiting caspase-1 enzymatic activity; or by blocking secreted IL-1β/IL-18 and their cognate receptors in autocrine/paracrine ways. CRID3 = cytokine release inhibitory drug 3; mAb = monoclonal antibody. See Figure 1 and 2 legends for expansion of other abbreviationsGrahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Activation of Inflammasomes by Respiratory Pathogens

The inflammasome-activating microbial components and the relevant inflammasomes are listed. AIM2 = absent in melanoma 2; CyaA = adenylate cyclase; ESAT-6 = 6kDa early secreted antigenic target; NLRC4 = nucleotide-binding oligomerization domain-like receptor, caspase activation and recruitment domain-containing 4; NLRP1b = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 1b; NLRP3 = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3; NLRP7 = nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 7.

Table Graphic Jump Location
Table 2 —Pharmacologic Targeting of the Inflammasome Pathway in Respiratory Diseases

CAPS = cryopyrin-associated periodic syndrome; FDA = US Food and Drug Administration; FEF25%-75% = forced expiratory flow between 25% and 75%; LAR = late asthmatic response; PD20 = provocative dose causing a 20% fall in FEV1; RA = rheumatoid arthritis; Refs = references; SVC = slow vital capacity.

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