key: cord-0007951-14b9hod9
authors: Xu, Fengying; Wen, Zongmei; Shi, Xueying; Fan, Jie
title: Inflammasome in the Pathogenesis of Pulmonary Diseases
date: 2018-09-05
journal: Inflammasomes: Clinical and Therapeutic Implications
DOI: 10.1007/978-3-319-89390-7_6
sha: 18e5ca6859a1131329eb3b2c61b66955d97aed20
doc_id: 7951
cord_uid: 14b9hod9

Lung diseases are common and significant causes of illness and death around the world. Inflammasomes have emerged as an important regulator of lung diseases. The important role of IL-1 beta and IL-18 in the inflammatory response of many lung diseases has been elucidated. The cleavage to turn IL-1 beta and IL-18 from their precursors into the active forms is tightly regulated by inflammasomes. In this chapter, we structurally review current evidence of inflammasome-related components in the pathogenesis of acute and chronic lung diseases, focusing on the “inflammasome-caspase-1-IL-1 beta/IL-18” axis.

In serving its primary function in gas exchange, the lung is constantly exposed to the outside world and is highly susceptible to all kinds of foreign matters. Lung diseases are common and significant causes of illness and death around the world. According to the World Health Organization (WHO) (http://www.who.int/mediacentre/ factsheets/fs310/en/), lower respiratory infections, chronic obstructive pulmonary disease (COPD), and tuberculosis are among the top 10 causes of death worldwide. Up to 7.73 million people died of these three diseases, accounting for nearly 14% of all death in 2015, not to mention other pulmonary diseases. In addition, lower respiratory infection is the leading cause of death in low-income economies.

The lack of effective treatment for many pulmonary diseases is at least partly due to our limited understanding of the pathobiology of these diseases. The lung has a defense mechanism consisting of physical barriers and immune cells against infection and injury. Upon insult, such as infection or tissue injury, the innate and adaptive immune system in the lung initiate a series of responses, followed by a period of normalization to restore homeostasis in the lung. Inflammation is one of the immediate responses of the innate immune system, in which cytokines constitute a significant part (Shaikh 2011). Interleukin (IL)-1 beta and its isoform IL-1 alpha are proinflammatory cytokines that exert pleiotropic effects on a variety of cells and play a vital role in acute and chronic inflammatory processes (Ren and Torres 2009) . IL-1 signal acting through the type 1 receptor IL-1R1, with the help of IL-1 receptor accessory protein, activates transcription factor nuclear factor-kappa B (NF-kappaB) and activator protein 1 (AP-1). Binding of IL-1 to type 2 receptor IL-1Ra does not lead to downstream signaling, and IL-1Ra is therefore considered a decoy receptor. IL-1 beta has important homeostatic functions under normal circumstances, while its overproduction is implicated in the pathophysiological changes in diverse disease states. IL-18 is another member of the IL-1 family. The IL-18 receptor (IL-18R) is a heterodimer consisting of IL-18R alpha and beta chains. IL-18 also mediates responses and activates NF-kappa B and AP-1, resulting in the production of IFN-gamma, essential for immunity against invading pathogens. In addition, IL-18 can act as a Th2 response inducer in some allergic diseases (Sedimbi et al. 2013) .

The important role of IL-1 beta and IL-18 in the inflammatory response of many diseases has been elucidated. The cleavage to turn IL-1 beta and IL-18 from their precursors into the active forms is tightly regulated. Over the past decade, researchers have found that inflammasome is the key component for this process, therefore, critical for the induction of a proper inflammatory response. The core sensor protein of inflammasome comes from the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) family. All NLR family members are classified into subfamilies based on the N-terminal domain they contain: NLRAs have transactivator activation domains (ADs); NLRBs have BIR (baculoviral inhibitor of apoptosis repeat) domains; NLRCs have CARD (caspase activation/recruitment domains); and NLRPs have PYD (pyrin domains) (Leissinger et al. 2014) . Of these, at least four NLR members (NLRP1, NLRP3, NLRC4, NLRB1) and absent in melanoma 2 (AIM2) can form inflammasome complexes with the adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and pro-caspase-1. Inflammasome formation results in the catalysis and activation of caspase-1, which in turn catalyzes the cytokine precursors (Lee et al. 2016) .

The detailed description of inflammasomes can be found elsewhere in this book. Normally, inflammasome formation requires a canonical two-step mechanism. Taking the NLRP3 inflammasome as an example: the first signal (e.g., TLR4 or other pattern recognition receptors) stimulates NF-kappa B and enhanced the expression and synthesis of NLRP3. The second signal induced NLRP3 inflammasome assembly. Common signal is provided by P2X purinoreceptor 7 (P2X7R) bond by adenosine triphosphate (ATP), K + efflux, lysosome destabilization caused by urate crystals, DNA and reactive oxygen species (ROS) generated in mitochondria, etc.

The discovery of inflammasome has changed our understanding of the pathogenesis of many diseases. Here we structurally summarize current evidence for the involvement of inflammasome in the pathogenesis of acute and chronic lung diseases, focusing on the "inflammasome-caspase-1-IL-1 beta/IL-18" axis.

Despite sophisticated advances in antibiotics, lung infection remains a significant cause of morbidity and mortality. As multidrug-resistant bacteria are emerging, it is a priority to better understand the mechanisms how our immune system combat pathogens. Researches involving the discussion of inflammasome in infectious pulmonary diseases are summarized and listed in Table 6 .1 according to publish date. The term "conflicting" in the column of "Contribution" means that not all the element studied was reported to take effect in a particular article. These terms are consistent throughout this chapter. (Hennet et al. 1992) . Also, IAV-infected human peripheral macrophages secreted IL-1 beta and IL-18 (Sareneva et al. 1998) . Similar results were found by Pirhonen et al. with primary human monocytes and differentiated macrophages. Besides, virus-induced IL-1 beta and IL-18 production was significantly blocked by a specific caspase-1 inhibitor (Pirhonen et al. 1999) . The role of IL-1 was further manifested. Schmitz et al. investigated the role of the IL-1R1 signaling during pulmonary antiviral immune responses in Il1r1 À/À mice. They demonstrated reduced inflammatory pathology, decreased activation and migration of CD4 + T cells, and greatly diminished immunoglobulin (Ig) M responses in Il1r1 À/À mice after influenza virus infection. In contrast, the activation of cytotoxic T lymphocytes and the IgG and IgA antibody responses was intact. Notably, the authors found significantly increased mortality in Il1r1 À/À mice after infection (Schmitz et al. 2005) .

The role of IL-18 has also been studied in gene knockout mice. Il18 À/À mice inoculated with IAV showed increased mortality with the occurrence of pathogenic changes including enhanced virus growth, massive inflammatory infiltration, and elevated nitric oxide production over the first 3 days after respiratory challenge (Liu et al. 2004 ). Thereafter, Denton et al. found that IL-18 deficiency was associated with delayed virus clearance from the lung and decreased cytokine production by CD8 + T lymphocytes (Denton et al. 2007 ). Thomas et al. showed that in vivo activation of the NLRP3 inflammasome by IAV RNA controlled the release of IL-1 beta and IL-18 and modulated the extent of lung pathology. Furthermore Nlrp3 À/À and Casp1 À/À mice were found more susceptible after IAV infection correlated with decreased cell recruitment and cytokine/chemokine production (Thomas et al. 2009 ). The in vivo role of NLRP3 inflammasome during influenza virus infection was verified around the same time. Mice lacking Nlrp3, ASC, or caspase-1, but not Nlrc4, exhibited increased mortality and a reduced immune response after influenza virus infection. Using poly I:C and ssRNA40 to analogize virus RNA, the authors concluded that NLRP3 inflammasome could be activated by RNA species dependent on lysosomal maturation and ROS .

In contrast to studies in certain cell types, like macrophages and epithelial cells, Ichinohe et al. found that ASC and caspase-1, but not NLRP3, were required for CD4 + and CD8 + T cell responses, as well as mucosal IgA secretion and systemic IgG responses to influenza virus infection. This study provided evidence of the requirement for the components of inflammasomes in adaptive immunity to virus infection in vivo (Ichinohe et al. 2009 ).

The mechanisms by which influenza virus activates the inflammasome have also been studied. Ichinohe et al. showed that the influenza virus M2 protein localized to the Golgi apparatus dependent on the pH gradient to stimulate the NLRP3 inflammasome in primed macrophages and dendritic cells (Ichinohe et al. 2010) . Increased ATP has been observed in the bronchoalveolar lavage fluid (BALF) of mice infected with IAV (Wolk et al. 2008) , which is usually believed to be a secondary signal in inflammasome activation and assembly.

Interaction Between Host and Microorganism On the other hand, pathogens have also evolved strategies to take advantage of inflammasome-related mechanisms to evade the host immune system. For example, Stasakova et al. reported that several NS1 mutant viruses induced much more biologically active IL-1 beta and IL-18 than wild-type viruses, therefore inducing rapid apoptosis in infected macrophages, which correlated with the enhanced activity of caspase-1 (Stasakova et al. 2005 ).

Mycobacterium is a genus of over 150 recognized species, including pathogens known to cause serious diseases in mammals, like tuberculosis (King et al. 2017) . Mycobacteria are aerobic and normally known as acid fast. The studies about infection with mycobacteria, in which inflammasome may take a part in were summarized.

IL-1 Signaling Studies in humans have shown that IL-1 was elevated in monocytederived macrophages stimulated in vitro (Giacomini et al. 2001) , in pleural fluid (Shimokata et al. 1991) , in cells obtained from BALF (Law et al. 1996; Tsao et al. 2000) , and in granulomas of patients with tuberculosis (Chensue et al. 1992) . It was reported that IL-1 beta production was induced by M. tuberculosis through pathways involving ERK, p38, and Rip2 after recognition by TLR2/TLR6 and NOD2 receptors (Kleinnijenhuis et al. 2009 ).

Genetic studies conducted by Bellamy et al. suggested that polymorphisms in IL-1R1 and possibly IL-1 alpha (but not IL-1 beta) significantly associated with tuberculosis (Bellamy et al. 1998 ). However, Wilkinson et al. reported no allele or genotype in IL-1Ra and IL-1 beta, single or in combination, was associated with an increased risk of tuberculosis (Wilkinson et al. 1999) .

In vivo animal studies using Il1r1 À/À and IL-1 beta À/À mice displayed acute mortality with increased bacterial burden in the lungs, suggesting an important role for IL-1 beta/IL-1R1 signaling response to Mycobacterium tuberculosis (Mayer-Barber et al. 2010). Il1r1 À/À mice showed defective granuloma formation containing fewer macrophages and lymphocytes, defective migration of immune cells, and a decrease in IFN-gamma production in the spleen. These changes were associated with increased mortality and an enhanced mycobacterial outgrowth in the lungs and distant organs (Juffermans et al. 2000) . IL-l alpha/beta double knockout mice developed significantly larger granulomas in lungs than wild-type mice after infection with M. tuberculosis, suggesting a protective role of IL-1 (Yamada et al. 2000) . More precisely, M. tuberculosis infection in Il1r1 À/À mice led to a profound defect of early control of infection with higher bacterial load in the lung and necrotic pneumonia. While pulmonary CD4 + and CD8 + T cell responses were unaffected (Fremond et al. 2007 ). However, in contrast, Master et al. showed that M. tuberculosis prevented inflammasome activation and subsequent IL-1 beta release and zmp1, which encoded a Zn 2+ metalloprotease, was responsible (Master et al. 2008) . Besides, Sugawara reported that Il1r1 À/À mice developed significantly larger granulomatous lesions with neutrophil infiltration in the lungs than wild-type mice did, and IFN-gamma production in spleen cells was lower in Il1r1 À/À mice (Sugawara et al. 2001 ).

IL-18 Signaling Il18 À/À mice developed marked granulomas compared with wildtype ones after M. tuberculosis infection. The granulomatous lesions could be inhibited significantly by exogenous recombinant IL-18. The splenic IFN-gamma levels were also lower in Il18 À/À mice (Sugawara et al. 1999) . Similarly, Il18 À/À mice were more prone to this infection than wild-type mice, and IFN-gamma production was significantly attenuated. Consistently, IL-18 transgenic mice were more resistant to the infection than their littermate mice, and IFN-gamma levels were increased (Kinjo et al. 2002) . However, Fremond et al. reported that unlike IL-1 beta, IL-18-dependent pathways seemed to be dispensable in response to M. tuberculosis infection (Fremond et al. 2007 ).

Inflammasome Activation Mycobacterium tuberculosis activated the NLRP3 inflammasome and induced a strong IL-1 beta response. The mechanism is not yet fully understood, but it was believed that M. tuberculosis induced inflammasome activation involving the export of the 6 kDa early secreted antigenic target (ESAT-6) through a functional protein secretion system ESX-1 (Mishra et al. 2010) . The function of ESX-1 in NLRP3 activation was further confirmed by Dorhoi et al. They also concluded that although NLRP3 inflammasome was critical for IL-1 beta secretion in macrophages, Nlrp3 À/À mice were not susceptible to M. tuberculosis infection, due to NLRP3-independent compensatory IL-1 beta production in lung parenchyma (Dorhoi et al. 2012) . Kleinnijenhuis et al. showed that the secretion of IL-1 beta in macrophage depended on the activation of P2X7R by endogenously ATP. However, they also suggested that constitutively expressed caspase-1 in monocyte need not be activated by M. tuberculosis (Kleinnijenhuis et al. 2009 ). Kurenuma et al. found that a genomic locus called "region of difference 1" (RD1) in Mycobacterium tuberculosis was essential for the activation of caspase-1 and subsequent secretion of IL-1 beta and IL-18 in macrophages. The activation was induced via RD1-dependent K + efflux independent of P2X7R (Kurenuma et al. 2009 ). While the above experiments were performed in an acute settings, McElvania et al. showed that M. tuberculosis induced IL-1 beta secretion in human and mouse macrophages in vitro, depending on ASC, caspase-1, and NLRP3, but not NLCR4. In addition, murine ASC protected the host during chronic M. tuberculosis infection, but the effects of caspase-1 and NLRP3 were dispensible (McElvania Tekippe et al. 2010) .

Mycobacterium marinum Mycobacterium marinum possesses virtually all of the virulence factors associated with M. tuberculosis, including the ESX-1 secretion system. Koo et al. identified that NLRP3, caspase-1, ASC, but not NLRC4, were required for the release of IL-1 beta and IL-18 after M. marinum or M. tuberculosis infection. Mostly important, they showed that mycobacteria-induced ESX-1-dependent lysosome secretion was essential to release, but not to synthesize IL-1 beta and IL-18 in vitro (Koo et al. 2008) . In vivo study confirmed the function of ESX-1 secretion system in activating NLRP3 inflammasome. However, the activation of NLRP3 inflammasome did not restrict bacterial growth, indicating a hostdetrimental role of this inflammatory pathway in mycobacterial infection (Carlsson et al. 2010) .

Mycobacterium abscessus Mycobacterium abscessus is one of the common species that causes disseminated infections in patients with cystic fibrosis. It has been reported that NLRP3 inflammasome activation contributed to the antimicrobial responses against M. abscessus in human macrophages, and its activation was dependent on dectin-1/Syk signaling .

Mycobacterium kansasii Live intracellular Mycobacterium kansasii has been reported to trigger the activation of the NLRP3 inflammasome, leading to caspase-1 activation and IL-1 beta secretion. Furthermore, K + efflux, lysosomal acidification, ROS production, and cathepsin B release played a role in this activation process ).

Some other pathogens that are common cause of respiratory tract and pulmonary infections are included in this part.

Streptococcus pneumonia Streptococcus pneumonia is a frequent colonizer in the upper respiratory tract and a leading cause of infections like pneumonia. McNeela et al. demonstrated that the activation of NLRP3 inflammasome was required for S. pneumonia or its virulence factor pneumolysin-mediated enhancement of IL-1 beta secretion in dendritic cells. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumonia (McNeela et al. 2010) . Similarly, Witzenrath et al. reported that S. pneumonia expressing hemolytic pneumolysin also induced NLRP3-dependent IL-1 beta production in human and murine mononuclear cells. The inflammasome pathway was protective maintaining the pulmonary microvascular barrier. Additionally, the results showed that inflammasome was not activated by bacterial mutants lacking pneumolysin, which could cause invasive disease clinically (Witzenrath et al. 2011) .

Staphylococcus aureus Staphylococcal α-hemolysin, an essential virulence factor of Staphylococcus aureus, has been shown to be required for the promotion of pneumonia in mouse models. It has long been proven that α-hemolysin could induce IL-1 beta secretion from human monocytes (Bhakdi et al. 1989 ). Furthermore, α-hemolysin can induce K + efflux in host cells (Jonas et al. 1994) . Craven et al. demonstrated that α-hemolysin activated the NLRP3 inflammasome resulting in the activation of caspase-1 and secretion of cytokines IL-1 beta and IL-18 in monocyte-derived cells from humans and mice. They also reported that α-hemolysin induced NLRP3-dependent cellular necrosis resulting in the release of endogenous dangerassociated molecular patterns (DAMPs) (Craven et al. 2009 ). Munoz-Planillo et al. further concluded that bacterial lipoproteins released by S. aureus were required for NLRP3 and caspase-1 activation triggered by αand β-hemolysins. Notably, caspase-1 activation was independent of ATP and P2X7R ).

Streptococcus pyogenes Harder et al. found that caspase-1 activation and IL-1 beta secretion were induced by live Streptococcus pyogenes. The toxin streptolysin O, NLRP3, and ASC were crucial for the process, while exogenous ATP or the P2X7R was not required (Harder et al. 2009 ).

Klebsiella pneumoniae NLRP3 inflammasome protected host during infection with Klebsiella pneumoniae, as inflammatory response decreased and mortality increased in Nlrp3 À/À and Asc À/À , but not Nlrc4 À/À mice. NLRP3 activated necrosis and triggered HMGB1 release in addition to IL-1 beta as well as IL-18 secretion in macrophages (Willingham et al. 2009 ). However, NLRC4 has also been found to be of importance for host survival, bacterial clearance, production of IL-1 beta, as well as neutrophil-mediated inflammation following pulmonary K. pneumoniae infection. Exogenous IL-1 beta partially rescued survival and restored neutrophil accumulation and cytokine/chemokine expression in the lungs of Nlrc4 À/À mice. Furthermore, Il1r1 À/À mice displayed a decrease in neutrophilic inflammation after infection (Cai et al. 2012 ).

Legionella pneumophila NLRC4 is shown to be important in the recognition, response, and resolution of infection with flagellated pathogens. Legionella pneumophila is a flagellated, Gram-negative, facultative intracellular pathogen. Amer et al. found that Legionella-induced NLRC4-dependent caspase-1 activation to restrict replication in macrophages (Amer et al. 2006) . ASC was found to be important for caspase-1 activation during L. pneumophila infection. Activation of caspase-1 via ASC did not require sense of flagellin by NLRC4. Besides, activation of caspase-1 in macrophages occurred independently of NLRP3 (Case et al. 2009 ). Slightly different, Pereira et al. found that NLRC4-dependent growth restriction of L. pneumophila was fully due to flagellin. In addition, L. pneumophila multiplied better in Nlrc4 À/À mice, and macrophages compared with that in caspase-1 deficient ones, suggesting a caspase-1-independent downstream of NLRC4 (Pereira et al. 2011b) . The importance of flagellin in activating NLRC4 was further tested, as nonflagellated Legionella bypassed the NLRC4 inflammasome-mediated growth restriction (Pereira et al. 2011a ). The type 4 secretion system was also suggested to be important for NLRC4-and caspase-1-dependent host response (Silveira and Zamboni 2010) .

Chlamydia pneumonia Studies have shown that in vitro Chlamydia pneumoniae infection could elicit IL-1 beta and IL-18 secretion (Netea et al. 2000; Kaukoranta-Tolvanen et al. 1996; Netea et al. 2004; Rupp et al. 2003 ). Shimada et al. demonstrated that C. pneumoniae infection in the lung induced NLRP3 inflammasome activation, leading to caspase-1-dependent IL-1 beta secretion. This inflammatory response was critical for host defense against infection, manifested by delayed bacterial clearance and increased mortality in caspase1 À/À mice, which could be rescued by recombinant IL-1 beta (Shimada et al. 2011) .

Nontypeable Haemophilus influenzae Nontypeable Haemophilus influenzae (NTHi) is the most common cause for bacterial exacerbations in COPD. Higher expression of NLRP3 and caspase-1 and a significant induction of IL-1 beta after NTHi stimulation were detected in a murine macrophage cell line. In addition, inhibition of caspase-1 in human lung tissue led to a significant reduction of IL-1 beta and IL-18 (Rotta Detto Loria et al. 2013).

Pseudomonas aeruginosa Reiniger et al. found rapid release of IL-1 beta in response to Pseudomonas aeruginosa. And Il1r À/À mice were susceptible to chronic P. aeruginosa lung infection (Reiniger et al. 2007 ). NLRC4 inflammasome was identified critical for optimal bacterial clearance in an in vivo model of lung infection with P. aeruginosa. The activation of caspase-1 and secretion of IL-1 beta were triggered by bacterial flagellin and type 3 secretion system (T3SS) (Franchi et al. 2007 ). The importance of NLRC4 and T3SS was further manifested by Sutterwala et al. and Miao et al. (Miao et al. 2008 ). Sutterwala et al. also reported that the P. aeruginosa strain expressing the exoenzyme U (ExoU, a T3SS effector) phospholipase was able to suppress caspase-1-mediated cytokine production via NLRC4, associated with more severe disease (Sutterwala et al. 2007 ). Pilin, a major component of the type 4 bacterial pilus, has also been reported to activate NLRC4 inflammasome via the T3SS in P. aeruginosa infection (Arlehamn and Evans 2011) . Activation of NLRC4 may depend not only on T3SS or flagellin but also on bacterial motility, as caspase-1 activation and IL-1 beta production were reduced when exposed to nonmotile P. aeruginosa in macrophages and dendritic cells (Patankar et al. 2013) . As an example, the temporal loss of P. aeruginosa motility has been described during chronic infections in patients with cystic fibrosis (Luzar et al. 1985; Mahenthiralingam et al. 1994) . Recently, Rimessi et al. demonstrated that flagellin of P. aeruginosa caused mitochondrial perturbation, which regulated NLRP3 activation and IL-1β and IL-18 processing by mitochondrial Ca2+ in human bronchial epithelial cells (Rimessi et al. 2015) .

Cryptococcus neoformans Recombinant IL-18 enhanced the elimination of live Cryptococcus neoformans from the lungs, prevented its dissemination to the brain, and increased the survival rate of infected mice. In addition, administration of neutralizing anti-IL-18 antibody exacerbated the infection (Kawakami et al. 1997) . They further reported that fungal clearance in the lung was reduced and the levels of IL-12 and IFN-gamma in the sera were significantly lower in Il18 À/À mice (Kawakami et al. 2000a ). IL-12 and IL-18 have been shown to synergistically increase the fungicidal activity against C. neoformans. A single administration of either IL-12 or IL-18 was not effective, while their combination significantly prolonged survival time of infected mice and reduced the fungal growth in lungs (Qureshi et al. 1999) . To discriminate the activity of IL-18 from that of counterpart cytokines like IL-12, Kawakami et al. conducted the experiment in IL-12p40 À/À mice. Neutralizing anti-IL-18 antibody almost completely abrogated IFN-gamma production, and host response in IL-12p40 and IL-18 double knockout mice was more profoundly impaired than in IL-12p40 À/À mice. Moreover, administration of IL-12 as well as IL-18 significantly restored the host resistance (Kawakami et al. 2000b ).

Aspergillus fumigatus The release of IL-1 beta was significantly increased from monocytes stimulated with hyphal fragments of Aspergillus fumigatus (Simitsopoulou et al. 2007 ). Further study found that hyphal fragments induced NLRP3 inflammasome assembly, caspase-1 activation, and IL-1 beta release from THP-1 cell line. The activation of NLRP3 required dectin-1/Syk signaling, K + efflux, and ROS production (Said-Sadier et al. 2010).

Acute respiratory distress syndrome (ARDS) is the acute onset of hypoxemia with bilateral infiltrates, in the absence of left atrial hypertension. In the 2012 Berlin definition, ALI was reassigned to be a mild type of ARDS. As it is not a single disease, we listed in Table 6 .2 the studies on ALI of different causes.

IL-1 Signaling IL-1 beta has been found in BALF from patients with ARDS (Pugin et al. 1996) . And it has been previously shown in rats that lung vascular permeability increases after short-term exposure to IL-1 alpha and IL-1 beta (Leff et al. 1994) . Ganter et al. demonstrated a role for the alphavbeta5 and alphavbeta6 integrins in mediating IL-1 beta-induced ALI (Ganter et al. 2008) .

Inflammasome Activation Our group demonstrated that lipopolysaccharides (LPS) activated NLRP3, enhanced the release of IL-1 beta, and promoted pyroptosis in alveolar macrophages. Meanwhile, IL-1 beta upregulated IL-1R1 through an autocrine mechanism (He et al. 2016) . Our group examined the role of the NLRP3 inflammasome in response to hemorrhagic shock in a mouse model of ALI. In our study, pulmonary endothelial cells were the primary source of IL-1 beta secretion after hemorrhagic shock. DAMPs (especially HMGB1) activated NADPH oxidase and caused thioredoxin-interacting protein to associate with NLRP3, leading to inflammasome activation. Notably, endothelial cells were also targets of IL-1 beta, which might cause a range of inflammatory molecules and an amplification of inflammation leading to ALI (Xiang et al. 2011) . We further showed that there existed a negative-feedback regulating the activation of inflammasome. While activating NLRP3 inflammasome, LPS also induced pyrin expression, which in turn suppressed the activation of inflammasome in mouse lungs. However, hemorrhagic shock suppressed IL-10 and pyrin expression, therefore significantly enhancing inflammasome activation and IL-1 beta secretion in macrophages and endothelial cells (Xu et al. 2013 ). Ventilation-induced lung injury (VILI) is a special type of ALI. Ventilation alone for a short period does not seem sufficient for mediator release and major lung injury in normal lungs (Wrigge et al. 2000) . However, mechanical ventilation may augment preexisting lung injury.

IL-1 Signaling A RCT showed that mechanical ventilation caused increased concentrations of IL-1 beta and IL-1Ra in BALF of ARDS patients (Ranieri et al. 1999 ). In basic research, combined LPS instillation and ventilation synergistically unregulated the production of IL-1 beta in rat lung tissues (Lin et al. 2007 ). Ventilation with a large tidal volume for 2 h induced the released of IL-1 beta in isolated, unperfused rat lungs with or without LPS injection (Tremblay et al. 1997 ). However, Ricard et al. reappraised the cytokine production in both in vivo and ex vivo ventilated rat lungs and were unable to detect the release of IL-1 beta (Ricard et al. 2001 ). In gene expression microarray studies, IL-1 beta has been identified as a candidate gene in rodent (mouse and rat) VILI models (Ma et al. 2005) .

Furthermore, recombinant IL-1Ra significantly lowered the concentration of albumin and elastase and decreased neutrophil infiltration in a rabbit model of VILI (Narimanbekov and Rozycki 1995) . Similarly, mice deficient in IL1R1 and rats treated with IL-1Ra showed preserved alveolar barrier function, reduced neutrophil recruitment, and decreased epithelial injury and permeability after mechanically ventilation .

A comprehensive gene expression analysis on peripheral blood from patients with ARDS and polymerase chain reaction and ELISA were performed. IL-1 beta and IL-18 transcripts were increased. And human plasma IL-18 levels were correlated with disease severity and mortality in critically ill patients. Besides, mechanical ventilation enhanced IL-18 levels in the lung, serum, and BALF in mice.

Genetic deletion of IL-18 or caspase-1 or treatment with IL-18 neutralizing antibody reduced lung injury and inflammation in response to ventilation (Dolinay et al. 2012) .

Inflammasome Activation More directly, Kuipers et al. showed that mRNA levels of ASC were higher in lung brush samples from patients after 5 h of ventilation. Also, ventilation increased relative expression of NLRP3 in alveolar macrophages. Besides, Yes mechanical ventilation increased the expression of NLRP3 and ASC, activated caspase-1, and promoted the release of IL-1 beta in mouse lung. In this process, uric acid was also released and may serve as the ligand for NLRP3. Additionally, mice deficient in NLRP3 or treatment with IL-1 receptor antagonist or glibenclamide displayed less VILI (Kuipers et al. 2012) . Using an in vitro model, Wu et al. also demonstrated that alveolar macrophages subjected to cyclic stretch released uric acid, which activated the NLRP3 inflammasome, and induced the release of IL-1 beta and IL-18. They determined that mitochondrial ROS generation was required for NLRP3 activation (Wu et al. 2013 ). It has long been reported that high-pressure mechanical ventilation significantly increased ATP release in BALF (Rich et al. 2003) . Another form of ALI associated with ventilation is hyperoxic acute lung injury (HALI). Kolliputi et al. reported that hyperoxia-induced K + efflux activated the NLRP3 inflammasome via the purinergic P2X7R to cause inflammation and HALI (Kolliputi et al. 2010) . Further, they demonstrated that Nlrp3 À/À mice had suppressed inflammatory response in BALF and lung tissue and blunted epithelial cell apoptosis to HALI (Fukumoto et al. 2013 Table 6 .3 lists the studies containing discussion of inflammasomes in smoking.

Cytokine regulation in the lung may be altered by smoke exposure. CS inhalation in smokers (healthy and COPD patients) induced IL-1 beta release in BALF (Kuschner et al. 1996) and in lung tissue and induced sputum . However, there are also studies reporting a lower level of IL-1 beta in macrophage from smokers before and after LPS stimulation (Sauty et al. 1994; Brown et al. 1989) . Pauwels et al. demonstrated that pulmonary inflammation after subacute CS exposure could be significantly attenuated by IL-1R1 knockout or neutralizing IL-1 alpha or IL-1 beta ). TLR4, MyD88, and IL-1R1 were reported to be involved in the inflammatory response to CS both in vitro and in vivo. Besides, CS-activated macrophages released IL-1 beta only in presence of ATP (Doz et al. 2008 ).

Signaling IL-18 signaling has also been demonstrated to be critical in the response to CS. CS was a potent stimulator of IL-18 and caspases-1. In addition, CS-induced inflammation was significantly decreased in Il18ra À/À mice (Kang et al. 2007 ).

Inflammasome Activation Direct evidence of inflammasome involvement came from Eltom et al. They demonstrated that NLRP3 and ASC, but not NLRC4 or AIM2, were required for CS-induced IL-1 beta and IL-18 release. Besides, mice deficient in caspase 1/11 had markedly attenuated levels of cytokines and neutrophil infiltration (Eltom et al. 2014 ). However, CS-induced inflammation and IL-1 alpha production were reported to occur independently of the NLRP3-caspase-1 axis .

Genetic deletion of the P2X7R or using a selective P2X7R inhibitor reduced CS-induced caspase-1 activation and IL-1 beta release during acute CS exposure in vivo. They reported that caspase-1 activity were higher in lung tissue from smokers (Eltom et al. 2011 ).

Articles containing discussion of inflammasomes in particle inhalation are summarized in Table 6 .4.

There are various kinds of particles in industrial and urban life, which can cause injuries to the lungs and pulmonary diseases. 

In vivo, lung IL-1 beta, IL-18, NLRP3, ASC, NLRC4, AIM2, caspase-1 Yes CS is closely related to COPD, which will be discussed in Sect. 6.3.2

Carbon black nanoparticles have been reported to cause caspase-1 activation, IL-1 beta release, and pyroptosis in alveolar macrophages (Reisetter et al. 2011) .

Inorganic materials can trigger NLRP3 response as well. Nano-TiO 2 activated NLRP3 inflammasome and induced IL-1 alpha and beta release in a phagocytosisindependent manner (Yazdi et al. 2010) . Nickel nanoparticles induced transient increase of IL-1 beta in rats (Morimoto et al. 2010) . Hamilton et al. demonstrated that nickel contamination in multiwalled carbon nanotubules activated NLRP3 via lysosomal disruption in primary macrophages (Hamilton et al. 2012) .

Urban particulate matter has been shown to induce IL-1 beta release in human primary bronchial epithelial cells (Fujii et al. 2001) . Furthermore, NLRP3 inflammasome was required for the production of IL-1 beta in vivo (Hirota et al. 2012) . Diesel exhaust particles (DEP) are a major component of the ambient particulate matter. It was shown that in vitro DEP stimulated IL-1 beta production in monocytes and macrophages (Pacheco et al. 2001; Yang et al. 1997 ) and in epithelial cells (Boland et al. 1999) . Il1r1 À/À mice and mice treated with IL-1Ra had reduced inflammation upon DEP exposure. However, the authors concluded that 

Listed in Table 6 .5 are the articles containing discussion on inflammasomes in COPD. COPD is an important lung and airway disease, and is increasing in incidence, especially in developing countries. COPD may affect over 200 million people worldwide (data from WHO). Long-term cigarette smoking is the most important risk factor that may initiate the disease. The evidence for the involvement of inflammasome in cigarette smoking has been discussed in previous section.

IL-1 Signaling Acute exposure to smoke elevated IL-1 beta, while 6 months of exposure did not. Mice deficient in IL-1R or treatment with pan-caspase or caspase-1 inhibitor were protected from inflammatory cell infiltration and matrix breakdown during acute smoke exposure. After 6 months of exposure, Il1r À/À mice were 65% protected against emphysema and completely protected against small airway remodeling (Churg et al. 2009 ). is present in exaggerated quantities in the lungs and the serum from patients with COPD (Kang et al. 2007 ). The levels of IL-18 in induced sputum of patients with COPD were also found to be elevated compared with healthy subjects and were inversely correlated with lung function (% predicted FEV 1 and FEV 1 /FVC ratio) (Rovina et al. 2009 ).

Furthermore, targeted overexpression of IL-18 in murine lungs resulted in widespread pulmonary inflammation, emphysema, mucus metaplasia, and airway remodeling through increased pulmonary CD4 + , CD8 + , CD19 + , and NK1.1 + cells No and type 1 cytokine (IFN-gamma), type 2 cytokine (IL-13), and type 17 cytokine (IL-17A) ).

Inflammasome Activation An increased level of ATP has been found in the lungs in a mouse model of smoke-induced acute lung inflammation and emphysema, and the increased ATP level correlated with pulmonary neutrophilia (Cicko et al. 2010) . Serum uric acid levels were higher in patients with more severe airflow limitation and in those having frequent exacerbations. Besides, high uric acid levels correlated with 30-day mortality, prolonged hospitalization, and more aggressive medical care in COPD patients with exacerbations (Bartziokas et al. 2014) .

Recently, Di Stefano et al. reported lack of NLRP3 inflammasome activation, with no differences in caspase-1 activation, IL-1 beta, or IL-18 levels in bronchial biopsies or in BALF in patients with stable COPD compared with control subjects (Di Stefano et al. 2014 ).

Asthma is another important lung disease, characterized by allergic reaction. Allergic inflammatory response in asthma is conventionally characterized by the activation of Th2 pathway. The importance of Th17 response has now been recognized (Table 6 .6).

IL-1 Signaling Serum IL-1beta levels and expression of IL-1 beta in the bronchial epithelium and submucosal macrophages were higher in patients with asthma compared with control subjects (Thomas and Chhabra 2003; Sousa et al. 1996) . In asthmatic patients, IL-1 beta concentrations in the sputum (Konno et al. 1996) and BALF (Broide et al. 1992 ) of symptomatic patients were significantly higher than that in asymptomatic subjects. BALF from patients with status asthmaticus had an elevated inflammatory activity due to the presence of excessive bioactive IL-1 beta (Tillie-Leblond et al. 1999 ). Hastie et al. stratified subjects by sputum granulocytes. Those patients with both increased eosinophils and neutrophils had the lowest lung function and increased symptoms. In this subset of patients, IL-1 beta level in the sputum was positively associated with neutrophil counts (Hastie et al. 2010) .

In a mouse model, IL-1 beta combined with TNF alpha can contribute to airway hyperresponsiveness and methacholine-induced bronchoconstriction (Horiba et al. 2011) . It was also reported that the ovalbumin-induced airway hypersensitivity response was significantly reduced in IL-1 alpha/beta-deficient mice whereas profoundly exacerbated in mice deficient in IL-1Ra, suggesting that IL-1 signaling was required for Th2 response (Nakae et al. 2003 ). In a model of mild asthma, IL-1R signaling was reported to be required, as eosinophilic inflammation and goblet cell hyperplasia were strongly reduced in Il1r1 À/À mice. In contrast, the IL-1R was not required in an allergic model with adjuvant (Schmitz et al. 2003) . Wang et al. applied a recombinant adenovirus expressing human IL-1ra in an ovalbumin-sensitized murine model of asthma. Single intranasal delivery before airway antigen challenge significantly decreased the severity of airway hyperresponsiveness, reduced pulmonary infiltration, and decreased peribronchial inflammation (Wang et al. 2006) .

Inflammasome Activation Direct evidence showed that allergic airway inflammation depended on NLRP3 inflammasome activation, as Th2 lymphocyte activation and cytokine production were reduced in mice deficient in NLRP3, ASC, or caspase-1. The critical role of IL-1R1 signaling was also confirmed in mice deficient in IL-1R1, IL-1 (Besnard et al. 2011) . Kim et al. recently demonstrated that levels of NLRP3 and caspase-1 in BALF from the patients with asthma were significantly higher than that in healthy subjects. Furthermore, suppression of mitochondrial ROS generation by NecroX-5 attenuated allergic airway inflammation associated with inhibition of NLRP3 inflammasome and caspase-1 activation in primary tracheal epithelial cells and mouse lung tissues. In addition, blockade of IL-1 beta substantially reduced airway inflammation and hyperresponsiveness in asthmatic mice (Kim et al. 2014) . It has been shown that gain of function SNPs in human NLRP3 are linked to food-induced anaphylaxis and aspirin-induced asthma (Hitomi et al. 2009 ). In multiple asthmatic models of mixed Th2/Th17 responses, serum amyloid A activated NLRP3 inflammasome to induce IL-1 beta secretion in dendritic cells and macrophages and promote CD4 + T cells to secrete IL-17A in an IL-1-dependent manner (Ather et al. 2011) . Similarly but differently, Martin et al. reported the importance of caspase-1 and IL-1R, but not NLRP3, for Th17 development in NO 2 -promoted allergic airway disease (Martin et al. 2013) . Also, Allen et al. determined that the NLRP3 inflammasome was not required in multiple allergic asthma models in mice. Besides, in all the models, the cytokines IL-1 beta and IL-18 in the lung were below the level of detection (Allen et al. 2012) . And Kool et al. suggested that NLRP3 and IL-1 beta did not contribute to the Th2 adjuvant effect of uric acid in mice (Kool et al. 2011) . Elevated ATP was found in the BALF of patients with asthma and ovalbuminchallenged asthmatic mice (Idzko et al. 2007 ). Consistently, P2X7R was found to be upregulated in acute and chronic asthmatic airway inflammation in mice and humans. Mice deficient in P2X7R or treated with specific P2X7R-antagonist had reduced airway inflammation in asthma models (Muller et al. 2011 ).

IPF is a progressive while irreversible disease, with a general poor prognosis. IPF is characterized by a histologic or radiologic pattern of usual interstitial pneumonia and progressive fibrosis of lung parenchyma. Bleomycin is a chemotherapeutic drug used clinically for a variety of human malignancies. However, a high dose of bleomycin can lead to lethal lung injury and pulmonary fibrosis in human patients, as well as in rodent models. Therefore rodent models of bleomycin-induced lung fibrosis have been widely used for the investigation of human IPF. Bleomycininduced fibrosis is also discussed in this section. Table 6 .7 listed the articles containing discussion of inflammasomes in IPF.

IL-1 Signaling Pan et al. observed that in IPF patients, cytokine IL-1 beta was positive in alveolar macrophages and type 2 pneumocytes in acute pulmonary fibrotic changes, but not in areas of old fibrosis, suggesting that IL-1 beta may play a role in the initial pulmonary fibrotic responses (Pan et al. 1996) . In vitro study found that alveolar macrophages from healthy human subjects released IL-1 beta after bleomycin challenge (Scheule et al. 1992) .

With a single base variation at position +2018 of the IL-1Ra gene, there is an increased risk of developing cryptogenic fibrosing alveolitis (Whyte et al. 2000) . Two other studies examining another polymorphism at intron 2 of the IL-1Ra gene found no association with increased susceptibility to IPF (Hutyrova et al. 2002; Riha et al. 2004) . Gasse et al. reported that in bleomycin-induced lung inflammation fibrosis depended on IL-1R1 signaling, as neutralization of IL-1 beta or specific blockage of IL-1R1 by antibody reduced bleomycin-induced pathology (Gasse et al. 2007 ). Overexpression of IL-1 beta for 7-10 days in rats was reported to induce an increase of TGF-beta in BALF and progressive interstitial fibrogenesis for the next 60 days, resembling human pulmonary fibrosis (Kolb et al. 2001) . IL-1 beta was further reported sufficient to induce IL-17 production, required for inflammatory response to bleomycin Gasse et al. 2011 ). (Kitasato et al. 2004 ). Hoshino et al. reported excessive IL-18 and IL-18R alpha expression in the lungs of patients with bleomycin-induced lung injury. They also found that intravenous administration of bleomycin induced the expression of IL-1 beta and IL-18 in the serum and lungs of mice. Moreover, lung injury, assessed by fibrosis score, hydroxyproline levels, and wet lung weight, was significantly attenuated in mice deficient in caspase-1, IL-18, or IL-18R alpha (Hoshino et al. 2009 ). However, Liu et al. failed to find an increase in serum and BALF levels of IL-18 in IPF patients (Liu et al. 2011) . Il18À/À mice showed much worse lung injuries after treatment with bleomycin, as assessed by survival rate, histological images, and leukocyte infiltration. Besides, pretreatment with IL-18 before bleomycin instillation appeared to be protective in lung injuries (Nakatani-Okuda et al. 2005) .

Inflammasome Activation Bleomycin-induced lung injury depended on NLRP3 inflammasome, as mice deficient in NLRP3 or caspase-1 displayed reduced neutrophil influx and IL-1 beta production in the lung. It was found that bleomycin-induced inflammasome activation is mediated by uric acid. Reduction of uric acid levels with inhibitor or uricase led to a decrease in IL-1 beta production, lung inflammation, and fibrosis. In addition, bleomycin-induced inflammation was IL-18-independent (Gasse et al. 2009 ). It has also been reported that mice lacking ASC had reduced neutrophil recruitment and a reduction in IL-1 beta production following bleomycin challenge (Gasse et al. 2007 ). Another example is from the research of statin. Numerous case reports suggested that statins could cause various types of interstitial lung diseases. Statin pretreatment enhances caspase-1-mediated responses in vivo and in vitro, which could be abolished in macrophages from mice deficient in NLRP3 (Xu et al. 2012) .

The role of caspase-1 in bleomycin-induced lung injury has also been investigated. Kuwano et al. reported that bleomycin enhanced caspase-1 activity in addition to elevated expression in inflammatory cells. They also demonstrated that a pan-caspase inhibitor zVAD-FMK was able to attenuate bleomycin-induced lung injuries (Kuwano et al. 2001) ATP levels were elevated in BALF from patients with IPF and from mice treated with bleomycin. Mice deficient in P2X7R or neutralized against ATP in the airways potently inhibit bleomycin-induced lung inflammation and remodeling ).

Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator and is the most common autosomal recessive disorder in western countries. Patients with cystic fibrosis often experience recurrent and chronic infections with Pseudomonas aeruginosa, as well as Staphylococcus aureus and Haemophilus influenzae (discussed in Sect. 1.1.3) .

Grassme et al. demonstrated the activation of caspase-1 and upregulation and membrane recruitment of ASC in the lungs of CF mice. These activations were associated with elevated levels of the signaling lipid-derived mediator, ceramide. Consistently, they also observed a normalization of IL-1 beta in the lungs after treatment with caspase-1 inhibitors (Grassme et al. 2014 ).

Crystalline silica is very common in occupational and environmental settings. Prolonged exposure in the workplace may lead to the development of silicosis, which is irreversible, progressive pulmonary fibrosis. Silica exposure is a highpriority public health concern. Alveolar macrophages, and their production of IL-1 beta, have been suggested to play a crucial role during the early inflammatory response after exposure to silica. Table 6 .8 lists the articles containing discussion of inflammasomes in silicosis.

IL-1 Signaling Silica induced a release of IL-1 beta in human alveolar macrophages in a caspase-1-dependent manner (Iyer et al. 1996) and in the lungs of silicaexposed mice (Davis et al. 1998) .

A polymorphism in IL-1Ra (+2018), but not IL-1 beta (+3953), was increased in a population of Caucasian coal miners with silicosis, indicating that this variant may confer susceptibility to developing silicosis (Yucesoy et al. 2001 ).

In addition, neutralizing IL-1 beta with monoclonal antibody reduced silicainduced inflammation and fibrosis by inhibiting mRNA expression of inflammatory and fibrogenic mediators (TGF beta, collagen I, and fibronectin) and modulating the Th1/Th2 balance toward a Th2-dominant response (Guo et al. 2013 ). The antifibrotic effect of inhibiting IL-1 beta was also reported by Piguet et al. where the administration of recombinant IL-1Ra reduced collagen deposition and the formation of fibrotic nodules in mice (Piguet et al. 1993 ). More directly, exposure of mice deficient in IL-1 beta to silica resulted in reduced lung inflammation, apoptosis, and significantly smaller silicotic lesions than in wild-type mice over a 12 weeks course (Srivastava et al. 2002) .

Inflammasome Activation Stimulation of macrophages with silica resulted in the secretion of IL-1 beta and IL-18 in an inflammasome-dependent manner, as macrophages deficient in NLRP3, ASC, or caspase-1 all displayed a marked defect in their ability to secrete cytokines. They also found that activation of the NLRP3 inflammasome by silica required both a K + efflux and the generation of ROS (Cassel et al. 2008) . Similarly, NLRP3 inflammasome activation was triggered by ROS generated by NADPH oxidase. In a model of asbestos inhalation, Nalp3 À/À mice showed diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production (Dostert et al. 2008) . Hornung et al. demonstrated that silica activated caspase-1 and induced the release of mature IL-1 beta in human PBMCs. IL-1 mediated the neutrophil influx after exposure to silica crystals. The phagocytosis of silica by macrophages resulted in lysosomal destabilization and subsequent rupture releasing proteolytic enzymes, such as cathepsin B into the cytosol, and the activation of the NLRP3 inflammasome (Hornung et al. 2008 ). In a case-control study, Ji et al. found that an SNP in the NLRP3 gene (rs1539019) was associated with a significant increase in coal workers pneumoconiosis in a Chinese population. This association was more pronounced in patients with stage I disease suggesting a potential role for the NLRP3 inflammasome in the development of silicosis (Ji et al. 2012) . NLPR3 activation has also been reported in nonmyeloid cells. NLRP3 activation, as well as activation of caspase-1, led to maturation and secretion of IL-1 beta in human bronchial epithelial cell lines and primary human bronchial epithelial cells (Peeters et al. 2013) .

ATP was released by macrophages after exposure to silica. The activation of the NLRP3 inflammasome relied on purinergic receptors and pannexin/connexin hemichannels. The use of specific P2X7 receptor inhibitors, or abrogation of ATP in primed human monocytic cell lines, was able to prevent silica-induced IL-1 beta production (Riteau et al. 2012) . This was further manifested in P2X7R knockout mice. Inflammatory cell infiltration and collagen deposition, cell apoptosis, and NF-κB activation as well as TGF-beta, nitric oxide, ROS, and IL-1 beta secretion were reduced in knockout mice (Moncao-Ribeiro et al. 2014).

Similar to silicosis, asbestosis often occurs as an occupational disease, particularly in developing countries. The inhalation of asbestos can also lead to lung cancer, mesothelioma, and pleural diseases. The articles containing discussion of inflammasomes in asbestosis are summarized in Table 6 .9.

IL-1 Signaling Cells recovered in BALF or alveolar macrophages from patients with asbestosis were reported to release higher levels of IL-1 beta in comparison with control groups (Zhang et al. 1993; Perkins et al. 1993) . In vivo models also demonstrated that asbestos exposure can result in enhanced IL-1 beta secretion in BALF (Haegens et al. 2007 ).

Inflammasome Activation Hillegass et al. reported that asbestos exposure was associated with an increase in NLRP3 expression and caspase-1 activation in mesothelial cells, leading to secreted IL-1 beta and IL-18, which could be attenuated by downregulation of NLRP3. They also reported that asbestos challenge had no significant effect on the NLRP1 or AIM2 inflammasomes (Hillegass et al. 2013) . Girardelli et al. reported that in a cohort of Italian patients with asbestos-induced mesothelioma, SNPs in the NLRP1, but not NLRP3 gene, may be associated with the disease (Girardelli et al. 2012) . Furthermore, Nlrp3 À/À mice were reported to have defects in IL-1 beta secretion and immune cell recruitment following asbestos exposure. However, NLRP3 was not critical in the chronic development of asbestos-induced mesothelioma, as a similar incidence of malignant mesothelioma in knockout mice (Chow et al. 2012 ). 

Pulmonary hypertension is characterized by sustained elevation of the pulmonary arterial pressure (>25 mm Hg). Prolonged high pressure in pulmonary artery system may lead to right ventricular failure. Table 6 .10 lists the studies on inflammasomes in pulmonary hypertension. In a mice model, hypoxia exposure caused pulmonary hypertension, including increased right ventricular systolic pressure and pulmonary vascular remodeling, along with activation of the NLRP3 inflammasome and caspase-1, as well as IL-1 beta and IL-18 production. These effects could be reversed with a superoxide dismutase mimetic (Villegas et al. 2013) . In another study, Asc À/À mice, but not Nlrp3 À/À , mice were resistant to hypoxia-induced pulmonary hypertension, as evidenced by no significant changes in levels of caspase-1, IL-18, or IL-1 beta, reduced right ventricular systolic pressure and reduced pulmonary vascular remodeling, indicating the possible involvement of alternate inflammasome complexes involving ASC (Cero et al. 2015 ).

Inflammasomes have emerged as an important regulator of the innate immune system and have significantly affected the understanding of the pathogenesis of many diseases. In this chapter, we reviewed the evidence of inflammasome-related components in the progression of pulmonary diseases. We can easily appreciate how the discovery of the inflammasome affects our understanding of the role of IL-1 and IL-18 signaling in lung disease. Still, in some diseases, the importance of inflammasomes has not been fully investigated. Besides, NLRP3 inflammasome in macrophage is currently the most clearly defined type. The potential of other inflammasomes in nonmyeloid cells needs to be further studied in the process of injury and recovery in lung diseases. 

Acute Lung Injury

133 6.3.4.1 Idiopathic Pulmonary Fibrosis (IPF)

The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA

Analysis of NLRP3 in the development of allergic airway disease in mice

Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf

Pseudomonas aeruginosa pilin activates the inflammasome

Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice

Serum uric acid as a predictor of mortality and future exacerbations of COPD

Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis

NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant

Release of interleukin-1 beta associated with potent cytocidal action of staphylococcal alpha-toxin on human monocytes

Diesel exhaust particles are taken up by human airway epithelial cells in vitro and alter cytokine production

Cytokines in symptomatic asthma airways

Cigarette smoking decreases interleukin 1 release by human alveolar macrophages

NLRC4 inflammasome-mediated production of IL-1beta modulates mucosal immunity in the lung against gram-negative bacterial infection

Hostdetrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection

Asc and Ipaf inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila

The Nalp3 inflammasome is essential for the development of silicosis

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Activation of an NLRP3 inflammasome restricts Mycobacterium kansasii infection

Immunohistochemical demonstration of interleukin-1 receptor antagonist protein and interleukin-1 in human lymphoid tissue and granulomas

NLRP3 promotes inflammation-induced skin cancer but is dispensable for asbestos-induced mesothelioma

The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling

Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema

Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells

Persistent overexpression of interleukin-1beta and tumor necrosis factor-alpha in murine silicosis

IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8+ T cells

Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD

Inflammasomeregulated cytokines are critical mediators of acute lung injury

Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis

Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica

Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent

receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke

Role of the inflammasome-caspase1/11-IL-1/18 axis in cigarette smoke driven airway inflammation: an insight into the pathogenesis of COPD

Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation

Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade

IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection

Particulate matter induces cytokine expression in human bronchial epithelial cells

NLRP3 deletion protects from hyperoxiainduced acute lung injury

Interleukin-1beta causes acute lung injury via alphavbeta5 and alphavbeta6 integrin-dependent mechanisms

IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice

Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis

IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis

Infection of human macrophages and dendritic cells with Mycobacterium tuberculosis induces a differential cytokine gene expression that modulates T cell response

NLRP1 polymorphisms in patients with asbestos-associated mesothelioma

Regulation of the inflammasome by ceramide in cystic fibrosis lungs

Neutralization of interleukin-1 beta attenuates silica-induced lung inflammation and fibrosis in C57BL/6 mice

Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo

NLRP3 inflammasome activation in murine alveolar macrophages and related lung pathology is associated with MWCNT nickel contamination

Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor

Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes

TLR4-upregulated IL-1beta and IL-1RI promote alveolar macrophage pyroptosis and lung inflammation through an autocrine mechanism

A kinetic study of immune mediators in the lungs of mice infected with influenza A virus

Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells

The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter

Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma

Effect of IL-1beta and TNF-alpha vs IL-13 on bronchial hyperresponsiveness, beta2-adrenergic responses and cellularity of bronchial alveolar lavage fluid

Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization

Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice

Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis

Inflammasome recognition of influenza virus is essential for adaptive immune responses

Influenza virus activates inflammasomes via its intracellular M2 ion channel

Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells

Silica-induced apoptosis mediated via scavenger receptor in human alveolar macrophages

Polymorphisms in inflammasome genes and risk of coal workers' pneumoconiosis in a Chinese population

Novel path to apoptosis: small transmembrane pores created by staphylococcal alpha-toxin in T lymphocytes evoke internucleosomal DNA degradation

Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis

IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation

IL-18 induces emphysema and airway and vascular remodeling via IFN-gamma

Growth of Chlamydia pneumoniae in cultured human peripheral blood mononuclear cells and induction of a cytokine response

IL-18 protects mice against pulmonary and disseminated infection with Cryptococcus neoformans by inducing IFN-gamma production

Reduced host resistance and Th1 response to Cryptococcus neoformans in interleukin-18 deficient mice

IL-18 contributes to host resistance against infection with Cryptococcus neoformans in mice with defective IL-12 synthesis through induction of IFN-gamma production by NK cells

NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation

Environmental reservoirs of pathogenic mycobacteria across the Ethiopian biogeographical landscape

Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12p40

Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis

Transcriptional and inflammasome-mediated pathways for the induction of IL-1beta production by Mycobacterium tuberculosis

Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis

The inflammasome mediates hyperoxia-induced alveolar cell permeability

Cytokine concentrations in sputum of asthmatic patients

ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection

An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma

Ventilator-induced lung injury is mediated by the NLRP3 inflammasome

The RD1 locus in the Mycobacterium tuberculosis genome contributes to activation of caspase-1 via induction of potassium ion efflux in infected macrophages

Dose-dependent cigarette smokingrelated inflammatory responses in healthy adults

Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor

Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis

Mycobacterium abscessus activates the NLRP3 inflammasome via Dectin-1-Syk and p62/SQSTM1

Regulation and function of the nucleotide binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 inflammasome in lung disease

Interleukin-1-induced lung neutrophil accumulation and oxygen metabolitemediated lung leak in rats

Investigating the role of nucleotide-binding oligomerization domain-like receptors in bacterial lung infection

Ventilator-induced injury augments interleukin-1beta production and neutrophil sequestration in lipopolysaccharide-treated lungs

Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity

Can circulating interleukin-18 differentiate between sarcoidosis and idiopathic pulmonary fibrosis?

Flagella and motility alterations in Pseudomonas aeruginosa strains from patients with cystic fibrosis: relationship to patient clinical condition

Bioinformatic identification of novel early stress response genes in rodent models of lung injury

Nonmotility and phagocytic resistance of Pseudomonas aeruginosa isolates from chronically colonized patients with cystic fibrosis

Interleukin-1 receptor and caspase-1 are required for the Th17 response in nitrogen dioxide-promoted allergic airway disease

Mycobacterium tuberculosis prevents inflammasome activation

Caspase-1 independent IL-1beta production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo

Granuloma formation and host defense in chronic Mycobacterium tuberculosis infection requires PYCARD/ASC but not NLRP3 or caspase-1

Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4

Pseudomonas aeruginosa activates caspase 1 through Ipaf

Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome

NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1beta

P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica

Expression of inflammation-related cytokines following intratracheal instillation of nickel oxide nanoparticles

A potential role for P2X7R in allergic airway inflammation in mice and humans

A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome

IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response

Protection against bleomycin-induced lung injury by IL-18 in mice

Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model

Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells

Chlamydia pneumoniae stimulates IFN-gamma synthesis through MyD88-dependent, TLR2-and TLR4-independent induction of IL-18 release

The influence of diesel exhaust particles on mononuclear phagocytic cell-derived cytokines: IL-10, TGF-beta and IL-1 beta

Co-expression of TNF alpha and IL-1 beta in human acute pulmonary fibrotic diseases: an immunohistochemical analysis

Flagellar motility is a key determinant of the magnitude of the inflammasome response to Pseudomonas aeruginosa

Role of IL-1alpha and the Nlrp3/caspase-1/IL-1beta axis in cigarette smoke-induced pulmonary inflammation and COPD

Silica induces NLRP3 inflammasome activation in human lung epithelial cells

The Nlrc4 inflammasome contributes to restriction of pulmonary infection by flagellated Legionella spp. that trigger pyroptosis

Activation of NLRC4 by flagellated bacteria triggers caspase-1-dependent and -independent responses to restrict Legionella pneumophila replication in macrophages and in vivo

Human alveolar macrophage cytokine release in response to in vitro and in vivo asbestos exposure

Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica

Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway

NLRP3/caspase-1-independent IL-1beta production mediates diesel exhaust particle-induced pulmonary inflammation

Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1

Combined effects of IL-12 and IL-18 on the clinical course and local cytokine production in murine pulmonary infection with Cryptococcus neoformans

Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial

Resistance to Pseudomonas aeruginosa chronic lung infection requires cystic fibrosis transmembrane conductance regulator-modulated interleukin-1 (IL-1) release and signaling through the IL-1 receptor

Induction of inflammasome-dependent pyroptosis by carbon black nanoparticles

Role of interleukin-1beta during pain and inflammation

Production of inflammatory cytokines in ventilatorinduced lung injury: a reappraisal

Adenosine triphosphate is released during injurious mechanical ventilation and contributes to lung edema

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis

ATP release and purinergic signaling: a common pathway for particle-mediated inflammasome activation

Nontypeable Haemophilus influenzae infection upregulates the NLRP3 inflammasome and leads to caspase-1-dependent secretion of interleukin-1beta -a possible pathway of exacerbations in COPD

Interleukin-18 in induced sputum: association with lung function in chronic obstructive pulmonary disease

Imbalanced secretion of IL-1beta and IL-1RA in Chlamydia pneumoniae-infected mononuclear cells from COPD patients

Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase

Influenza A virus-induced IFN-alpha/ beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells

Cytostatic activity of alveolar macrophages from smokers and nonsmokers: role of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha

Bleomycin stimulation of cytokine secretion by the human alveolar macrophage

The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model

Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection

Cytokines & their physiologic and pharmacologic functions in inflammation: a review

Caspase-1 dependent IL-1beta secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection

Cytokine content in pleural effusion. Comparison between tuberculous and carcinomatous pleurisy

Pore formation triggered by Legionella spp. is an Nlrc4 inflammasome-dependent host cell response that precedes pyroptosis

Expression of immunomodulatory genes in human monocytes induced by voriconazole in the presence of Aspergillus fumigatus

Expression of interleukin-1 beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic bronchial epithelium

Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice

Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18

Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice

Role of interleukin (IL)-1 type 1 receptor in mycobacterial infection

Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome

The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1

Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmaticus

Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model

Imbalances between tumor necrosis factor-alpha and its soluble receptor forms, and interleukin-1beta and interleukin-1 receptor antagonist in BAL fluid of cavitary pulmonary tuberculosis

Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome

Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma

Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms

Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis

NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways

Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent

The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia

Influenza A virus inhibits alveolar fluid clearance in BALB/c mice

Effects of mechanical ventilation on release of cytokines into systemic circulation in patients with normal pulmonary function

Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury

Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells

Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation

Hemorrhagic shock augments Nlrp3 inflammasome activation in the lung through impaired pyrin induction

Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice

Effects of diesel exhaust particles on the release of interleukin-1 and tumor necrosis factor-alpha from rat alveolar macrophages

Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1alpha and IL-1beta

Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis

Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure