The Inflammasome NLR Family Pyrin Domain-Containing Protein 3 (NLRP3) as a Novel Therapeutic Target for Idiopathic Pulmonary Fibrosis
2022; Elsevier BV; Volume: 192; Issue: 6 Linguagem: Inglês
10.1016/j.ajpath.2022.03.003
ISSN1525-2191
AutoresRuben Manuel Luciano Colunga Biancatelli, Pavel Solopov, John D. Catravas,
Tópico(s)Gout, Hyperuricemia, Uric Acid
ResumoIdiopathic pulmonary fibrosis (IPF) is a dramatic disease without cure. The US Food and Drug Administration–approved drugs, pirfenidone and nintedanib, only slow disease progression. The clinical investigation of novel therapeutic approaches for IPF is an unmet clinical need. Nucleotide-binding oligomerization domain-like receptor or NOD-like receptors are pattern recognition receptors capable of binding a large variety of stress factors. NLR family pyrin domain-containing protein 3 (NLRP3), once activated, promotes IL-1β, IL-18 production, and innate immune responses. Multiple reports indicate that the inflammasome NLRP3 is overactivated in IPF patients, leading to increased production of class I IL and collagens. Similarly, data from animal models of pulmonary fibrosis confirm the role of NLRP3 in the development of chronic lung injury and pulmonary fibrosis. This report provides a review of the evidence of NLRP3 activation in IPF and of NLRP3 inhibition in different animal models of fibrosis, and highlights the recent advances in direct and indirect NLRP3 inhibitors. Idiopathic pulmonary fibrosis (IPF) is a dramatic disease without cure. The US Food and Drug Administration–approved drugs, pirfenidone and nintedanib, only slow disease progression. The clinical investigation of novel therapeutic approaches for IPF is an unmet clinical need. Nucleotide-binding oligomerization domain-like receptor or NOD-like receptors are pattern recognition receptors capable of binding a large variety of stress factors. NLR family pyrin domain-containing protein 3 (NLRP3), once activated, promotes IL-1β, IL-18 production, and innate immune responses. Multiple reports indicate that the inflammasome NLRP3 is overactivated in IPF patients, leading to increased production of class I IL and collagens. Similarly, data from animal models of pulmonary fibrosis confirm the role of NLRP3 in the development of chronic lung injury and pulmonary fibrosis. This report provides a review of the evidence of NLRP3 activation in IPF and of NLRP3 inhibition in different animal models of fibrosis, and highlights the recent advances in direct and indirect NLRP3 inhibitors. More than 40% of all deaths recorded globally can be attributed to increased accumulation of collagen in organs and tissues, culminating in fibrotic disease.1Wynn T.A. Cellular and molecular mechanisms of fibrosis.J Pathol. 2008; 214: 199-210Crossref PubMed Scopus (2973) Google Scholar Idiopathic pulmonary fibrosis (IPF), the most common interstitial lung disease, has increasing trends and poor outcomes, with 3 to 5 years of life expectancy after diagnosis.2Thomeer M.J. Costabe U. Rizzato G. Poletti V. Demedts M. Comparison of registries of interstitial lung diseases in three European countries.Eur Respir J Suppl. 2001; 32: 114s-118sPubMed Google Scholar,3Olson A.L. Swigris J.J. Lezotte D.C. Norris J.M. Wilson C.G. Brown K.K. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003.Am J Respir Crit Care Med. 2007; 176: 277-284Crossref PubMed Scopus (334) Google Scholar Pirfenidone and nintedanib, the only US Food and Drug Administration–approved drugs, improve IPF patients' quality of life and slow disease progression, but a cure is still missing.4Bonella F. Stowasser S. Wollin L. Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib.Drug Des Devel Ther. 2015; 9: 6407-6419PubMed Google Scholar,5Albera C. Costabel U. Fagan E.A. Glassberg M.K. Gorina E. Lancaster L. Lederer D.J. Nathan S.D. Spirig D. Swigris J.J. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function.Eur Respir J. 2016; 48: 843-851Crossref PubMed Scopus (112) Google Scholar Although the exact cause of IPF is unknown, most theories suggest dysfunction in the wound-healing response,6Chambers R.C. Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling.Eur Respir Rev. 2008; 17: 130Google Scholar genetic predisposition,7Kropski J.A. Blackwell T.S. Loyd J.E. The genetic basis of idiopathic pulmonary fibrosis.Eur Respir J. 2015; 45: 1717Crossref PubMed Scopus (112) Google Scholar endoplasmic reticulum (ER) stress,8Burman A. Tanjore H. Blackwell T.S. Endoplasmic reticulum stress in pulmonary fibrosis.Matrix Biol. 2018; 68-69: 355-365Crossref PubMed Scopus (101) Google Scholar and/or exaggerated immune responses with fibroblast activation.9Desai O. Winkler J. Minasyan M. Herzog E.L. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis.Front Med. 2018; 5: 43Crossref PubMed Scopus (135) Google ScholarMultiple reports underline the role of the inflammasomes in IPF, suggesting that their activity may be a driving factor for the development of fibrosis and a potential target for new therapies. Inflammasomes are pattern recognition receptors (PRRs)—nucleotide-binding oligomerization domain-like receptors or NOD-like receptors (NLRs)—capable of binding a large number of molecular motifs of microorganisms, as well as alarm signals produced by immune cells (pathogen-associated molecular patterns and damage-associated molecular patterns).10Martinon F. Tschopp J. NLRs join TLRs as innate sensors of pathogens.Trends Immunol. 2005; 26: 447-454Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar The discovery of the inflammasome in early 2000 also revealed its essential role in augmenting the innate immune response in toll-like receptor–mediated signaling.11Tschopp J. Martinon F. Burns K. NALPs: a novel protein family involved in inflammation.Nat Rev Mol Cell Biol. 2003; 4: 95-104Crossref PubMed Scopus (590) Google Scholar The most studied of the inflammasome family, NLR family pyrin domain-containing protein 3 (NLRP3), is encoded by the gene NLRP3 on the long arm of chromosome 1.12Hoffman H.M. Wright F.A. Broide D.H. Wanderer A.A. Kolodner R.D. Identification of a locus on chromosome 1q44 for familial cold urticaria.Am J Human Genetics. 2000; 66: 1693-1698Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar NLRP3 was initially found in macrophages,13Keyel P.A. Heid M.E. Salter R.D. Macrophage responses to bacterial toxins: a balance between activation and suppression.Immunol Res. 2011; 50: 118-123Google Scholar but later reports detected high levels in multiple other cells, including epithelial and endothelial cells.14Bai B. Yang Y. Wang Q. Li M. Tian C. Liu Y. Aung L.H.H. Li P-f Yu T. Chu X-m NLRP3 inflammasome in endothelial dysfunction.Cell Death Dis. 2020; 11: 776Crossref PubMed Scopus (117) Google Scholar,15Kostadinova E. Chaput C. Gutbier B. Lippmann J. Sander L.E. Mitchell T.J. Suttorp N. Witzenrath M. Opitz B. NLRP3 protects alveolar barrier integrity by an inflammasome-independent increase of epithelial cell adherence.Sci Rep. 2016; 6: 30943Google Scholar It participates in the innate immune response via the secretion of IL-1 family cytokines. Under basal conditions, NLRP3 resides in the mitochondria and endoplasmic reticulum, but during stress it migrates to perinuclear regions.16Zhou R. Yazdi A.S. Menu P. Tschopp J. A role for mitochondria in NLRP3 inflammasome activation.Nature. 2011; 469: 221-225Crossref PubMed Scopus (3304) Google ScholarThe inflammasome differs from other PRRs as it displays the rare feature of recognizing a wide range of unrelated bacterial, viral, and fungal pathogen-associated molecular patterns as well as endogenous damage-associated molecular patterns in sterile inflammation or following exposure to environmental irritants. Indeed, NLRP3 is activated by multiple stimuli, including mitochondrial, lysosomal, ER, and oxidative stresses, as well as ion flux and DNA damage.17Chen X. Guo X. Ge Q. Zhao Y. Mu H. Zhang J. ER stress activates the NLRP3 inflammasome: a novel mechanism of atherosclerosis.Oxid Med Cell Longev. 2019; 2019: 3462530Google ScholarVarious animal models have underlined NLRP3’s role in the fibrotic process,18Colunga Biancatelli R.M.L. Solopov P. Dimitropoulou C. Catravas J.D. Age-dependent chronic lung injury and pulmonary fibrosis following single exposure to hydrochloric acid.Int J Mol Sci. 2021; 22: 8833Google Scholar, 19Stout-Delgado H.W. Cho S.J. Chu S.G. Mitzel D.N. Villalba J. El-Chemaly S. Ryter S.W. Choi A.M.K. Rosas I.O. Age-dependent susceptibility to pulmonary fibrosis is associated with NLRP3 inflammasome activation.Am J Respir Cell Mol Biol. 2016; 55: 252-263Crossref PubMed Scopus (85) Google Scholar, 20Li Y. Li H. Liu S. Pan P. Su X. Tan H. Wu D. Zhang L. Song C. Dai M. Li Q. Mao Z. Long Y. Hu Y. Hu C. Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3 inflammasome activation.Mol Immunol. 2018; 99: 134-144Crossref PubMed Scopus (87) Google Scholar and clinical investigations have identified the NLRP3/IL-1 pathway in chronic lung diseases.21Lasithiotaki I. Giannarakis I. Tsitoura E. Samara K.D. Margaritopoulos G.A. Choulaki C. Vasarmidi E. Tzanakis N. Voloudaki A. Sidiropoulos P. Siafakas N.M. Antoniou K.M. NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung.Eur Respir J. 2016; 47: 910Crossref PubMed Scopus (61) Google Scholar,22Jäger B. Seeliger B. Terwolbeck O. Warnecke G. Welte T. Müller M. Bode C. Prasse A. The NLRP3-inflammasome-caspase-1 pathway is upregulated in idiopathic pulmonary fibrosis and acute exacerbations and is inducible by apoptotic A549 cells.Front Immunol. 2021; 12: 642855Google Scholar These proinflammatory cytokines participate in epithelial-to-mesenchymal transformation and in the production and deposition of collagen.23Kitasato Y. Hoshino T. Okamoto M. Kato S. Koda Y. Nagata N. Kinoshita M. Koga H. Yoon D.Y. Asao H. Ohmoto H. Koga T. Rikimaru T. Aizawa H. Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis.Am J Respir Cell Mol Biol. 2004; 31: 619-625Crossref PubMed Scopus (70) Google ScholarThus, the investigation of direct and indirect NLRP3 inhibitors for lung disease represents an unmet clinical need. This review highlights NLRP3 involvement in lung fibrosis, collagen deposition, and mesenchymal transformation, and summarize the therapeutic advances in the development of NLRP3 inhibitors.NLRP3 Structure and AssemblyNLRP3 is a PRR located in the cytoplasm and is able to sense microbes and other danger signals. NLRP3 exists as inactive monomers expressed in the cytoplasm or on the surface of mitochondria and ER, as aggregated, active oligomers. The exact mechanism that leads to NLRP3 assembly remains unclear. However, recent reports have provided a deeper understanding of the activation process.The active inflammasome consists of a detector (NLRP3), an adaptor (ASC; part of apoptosis-associated speck-like protein), and an effector, caspase 1.The detector NLRP3 is a pyrin-like protein, with an amino-terminal pyrin domain (PYD), a central nucleotide binding site domain, and a carboxy-terminal leucin-rich repeat motif. The adaptor ASC and its caspase activation and recruitment domain moderate the interaction of NLRP3 with other proteins, and the formation of large complexes, among which is its crucial binding with the amino-terminal domain of caspases.24Srinivasula S.M. Poyet J.-L. Razmara M. Datta P. Zhang Z. Alnemri E.S. The pyrin-card protein ASC is an activating adaptor for caspase-1.J Biol Chem. 2002; 277: 21119-21122Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar Caspase 1, or IL-1 converting enzyme—the effector—is a highly conserved enzyme that cleaves precursors of IL-1β, IL-18, and gasdermin D into their activated forms.25Franchi L. Eigenbrod T. Muñoz-Planillo R. Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis.Nat Immunol. 2009; 10: 241-247Crossref PubMed Scopus (1267) Google ScholarThe domains of NLRP3 possess self-regulated activity that coordinates protein oligomerization and structural rearrangements required for its functionality. The central part on NLRP3 is divided into the nucleotide binding site and NACHT [neuronal apoptosis inhibitor proteins (NAIP), class II transactivator (CIITA), HET-E, and topoisomerase 1 (TP-1)] domains, the latter exerting both apoptotic and antiapoptotic ATPase activity.26Koonin E.V. Aravind L. The NACHT family – a new group of predicted NTPases implicated in apoptosis and MHC transcription activation.Trends Biochem Sci. 2000; 25: 223-224Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar The third domain, leucin-rich repeat, senses danger signals and is similarly expressed by multiple other innate immune receptors. The ATPase activity of the central domain promotes its assembly, whereas the leucin-rich repeat is capable of folding toward the central domain, interfering with this process.27Duncan J.A. Bergstralh D.T. Wang Y. Willingham S.B. Ye Z. Zimmermann A.G. Ting J.P.-Y. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling.Proc Natl Acad Sci U S A. 2007; 104: 8041Crossref PubMed Scopus (321) Google ScholarDuring stress, the central domain (NACHT) mediates the oligomerization of multiple NLRP3 proteins. ASC is recruited, and after its link with the PYD domains, forms helical ASC filaments. Finally, ASC filaments unite into a singular macromolecule capable of recruiting inactive caspase-1, which in this bound conformation self-cleaves, releases p20-p10 fragments, and acquires its active enzymatic form.28Boucher D. Monteleone M. Coll R.C. Chen K.W. Ross C.M. Teo J.L. Gomez G.A. Holley C.L. Bierschenk D. Stacey K.J. Yap A.S. Bezbradica J.S. Schroder K. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity.J Exp Med. 2018; 215: 827-840Crossref PubMed Scopus (241) Google ScholarNLRP3 RegulationThe assembly and activation of NLRP3 is highly regulated. Indeed, NLRP3 activation requires a two-step process: first priming and later activation. Priming is necessary for two main functions; the first one is to increase the expression of its components, NLRP3, caspase-1, and pro–IL-1β. The transcription of these proteins is up-regulated by toll-like receptors, by NOD2 receptors, or through cytokines tumor necrosis factor-α and IL-1β that promote NF-κB activation and gene transcription.29Bauernfeind F.G. Horvath G. Stutz A. Alnemri E.S. MacDonald K. Speert D. Fernandes-Alnemri T. Wu J. Monks B.G. Fitzgerald K.A. Hornung V. Latz E. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.J Immunol. 2009; 183: 787-791Crossref PubMed Scopus (1781) Google Scholar The second is for NLRP3 post-translational modifications, which maintain NLRP3 into an autosuppressed and inactive, but signal competent, state. These post-translational modifications include ubiquitylation, phosphorylation, and sumoylation. While priming guarantees the proper cellular microenvironment to sustain NLRP3 function, activation occurs through the recognition of molecular patterns. As mentioned, an incredibly large number of pathogen-associated molecular patterns, damage-associated molecular patterns, and chemical signals can promote NLRP3 activation. As a result, NLRP3 is involved in the response to insults and in the cellular stress response. However, the mechanism by which the NLRP3 inflammasome senses stress is not completely understood. In addition, because many overlapping and interrelated pathways culminate in NLRP3 activation, a unique consensus is missing. Indeed, several cellular processes lead to NLRP3 activation, such as ionic imbalances (K+ efflux, Cl− efflux, and Ca2+ flux), lysosomal disruption, mitochondrial dysfunction, metabolic changes, endoplasmic reticulum stress, and others.30Swanson K.V. Deng M. Ting J.P.Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics.Nat Rev Immunol. 2019; 19: 477-489Crossref PubMed Scopus (1404) Google Scholar It is clear then, that in contrast to most PRRs, which promote transcription of inflammatory mediators, NLRP3 participates in the post-transcriptional activation of the IL-1 class family, providing a last checkpoint before the inflammatory response.NLRP3 in the LungLungs are constantly exposed to inhaled microbes, particulates, and host-derived danger signals, thus requiring the presence of an active, but regulated, innate immune response, able to guarantee protection from disease. The lung contains various families of innate immune PPRs, like toll-like receptor, RIG-I–like receptors, and NOD-like receptors (NLRs), that mediate the initial signaling and regulation of inflammatory mediators.31Xiang M. Fan J. Pattern recognition receptor-dependent mechanisms of acute lung injury.Mol Med. 2010; 16: 69-82Crossref PubMed Scopus (76) Google Scholar Alveolar macrophages, as well as alveolar epithelial and endothelial cells, express high levels of NLRP3 mRNA.32Peeters P.M. Perkins T.N. Wouters E.F. Mossman B.T. Reynaert N.L. Silica induces NLRP3 inflammasome activation in human lung epithelial cells.Part Fibre Toxicol. 2013; 10: 3Crossref PubMed Scopus (121) Google Scholar, 33Ito H. Kimura H. Karasawa T. Hisata S. Sadatomo A. Inoue Y. Yamada N. Aizawa E. Hishida E. Kamata R. Komada T. Watanabe S. Kasahara T. Suzuki T. Horie H. Kitayama J. Sata N. Yamaji-Kegan K. Takahashi M. NLRP3 inflammasome activation in lung vascular endothelial cells contributes to intestinal ischemia/reperfusion-induced acute lung injury.J Immunol. 2020; 205: 1393-1405Google Scholar, 34Gwyer Findlay E. Hussell T. Macrophage-mediated inflammation and disease: a focus on the lung.Mediators Inflamm. 2012; 2012: 140937Crossref PubMed Scopus (57) Google Scholar Thus, the whole alveolocapillary structure shares a common defense mechanism that is highly conserved against multiple infective and noninfective stimuli (Figure 1).NLRP3 is activated in animal models of silica/asbestos exposure; mice lacking either NLRP3 or ASC do not display increased IL-1β, inflammatory cells in the bronchoalveolar lavage fluid (BALF), or collagen deposition.35Cassel S.L. Eisenbarth S.C. Iyer S.S. Sadler J.J. Colegio O.R. Tephly L.A. Carter A.B. Rothman P.B. Flavell R.A. Sutterwala F.S. The Nalp3 inflammasome is essential for the development of silicosis.Proc Natl Acad Sci U S A. 2008; 105: 9035-9040Crossref PubMed Scopus (673) Google Scholar,36Dostert C. Pétrilli V. Van Bruggen R. Steele C. Mossman B.T. Tschopp J. 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These cytokines are crucial in the innate immune response, induction of hyperpyrexia, expression of adhesion molecules, as well as in mediating hyperalgesia, vasodilation, and hypotension.Nine of these cytokines occur in a single cluster of chromosome 2, probably originating from gene duplications of an IL-1β ligand of ancestral origin (IL-1α, IL-1β, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL37, IL-38, and IL-1Ra).38Rivers-Auty J. Daniels M.J.D. Colliver I. Robertson D.L. Brough D. Redefining the ancestral origins of the interleukin-1 superfamily.Nat Commun. 2018; 9: 1156Crossref PubMed Scopus (51) Google Scholar IL-1α, Il-1β, and IL-1Ra (the competing receptor antagonist) bind the IL-1R receptor, whose signaling is mediated initially by toll- and IL-1R–like domains on adaptor proteins, and later by phosphorylation of myeloid differentiation primary response gene 88 and IL-1 receptor-activated protein kinases.39Weber A. Wasiliew P. Kracht M. Interleukin-1 (IL-1) pathway.Sci Signaling. 2010; 3: cm1Crossref PubMed Scopus (565) Google Scholar Alternatively, IL-18 and IL-33 may originate from another genetic locus, but share high structural similarity with typical IL-1 isoforms, are internalized by IL-1 receptor accessory protein (coreceptor or IL-1R), and, thus, have been classified as members of the same family.Myeloid differentiation primary response gene 88 and IL-1 receptor-activated protein kinases interact with tumor necrosis factor-α receptor-associated factor 6, transforming growth factor-β–activated protein kinase, and mitogen activated protein kinase 3 (MAPK3) and lead to the transcription of NF-κB, activator protein-1 (AP-1), c-Jun N-terminal kinase, and p38.40Fields J.K. Günther S. Sundberg E.J. Structural basis of IL-1 family cytokine signaling.Front Immunol. 2019; 10: 1412Crossref PubMed Scopus (99) Google ScholarIL-18 and IL-18Ra expression is increased in patients with IPF, and experimental administration of IL-18 in mice augments the progressive deposition of extracellular matrix and the development of fibrosis, underlining the important role of IL-18 in lung pathology.23Kitasato Y. Hoshino T. Okamoto M. Kato S. Koda Y. Nagata N. Kinoshita M. Koga H. Yoon D.Y. Asao H. Ohmoto H. Koga T. Rikimaru T. Aizawa H. Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis.Am J Respir Cell Mol Biol. 2004; 31: 619-625Crossref PubMed Scopus (70) Google Scholar Also, IL-18 triggers fibroblast senescence, and its secretory phenotype (senescence-associated secretory phenotype) is associated with worse outcomes in lung fibrosis.41Zhang L.M. Zhang J. Zhang Y. Fei C. Wang L. Yi Z.W. Zhang Z.Q. Interleukin-18 promotes fibroblast senescence in pulmonary fibrosis through down-regulating Klotho expression.Biomed Pharmacother. 2019; 113: 108756Google Scholar Similarly, levels of IL-1 cytokines are chronically overexpressed in patients with chronic obstructive pulmonary disease, asthma, and IPF.42Osei E.T. Brandsma C.-A. Timens W. Heijink I.H. Hackett T.-L. Current perspectives on the role of interleukin-1 signaling in the pathogenesis of asthma and COPD.Eur Respir J. 2019; 55: 1900563Google Scholar,43Smith D.R. Kunkel S.L. Standiford T.J. Rolfe M.W. Lynch 3rd, J.P. Arenberg D.A. Wilke C.A. Burdick M.D. Martinez F.J. Hampton J.N. Increased interleukin-1 receptor antagonist in idiopathic pulmonary fibrosis: a compartmental analysis.Am J Respir Crit Care Med. 1995; 151: 1965-1973Crossref PubMed Scopus (38) Google Scholar In the lung, IL-1β participates in inflammation, white blood cell migration, disruption of elastin fibers, and collagen deposition.44Lappalainen U. Whitsett J.A. Wert S.E. Tichelaar J.W. Bry K. Interleukin-1β causes pulmonary inflammation, emphysema, and airway remodeling in the adult murine lung.Am J Respir Cell Mol Biol. 2005; 32: 311-318Crossref PubMed Scopus (355) Google Scholar These effects are in part mediated by IL-17A pathways.45Wilson M.S. Madala S.K. Ramalingam T.R. Gochuico B.R. Rosas I.O. Cheever A.W. Wynn T.A. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent.J Exp Med. 2010; 207: 535-552Crossref PubMed Scopus (499) Google Scholar,46Park M.-J. Moon S.-J. Lee E.-J. Jung K.-A. Kim E.-K. Kim D.-S. Lee J.-H. Kwok S.-K. Min J.-K. Park S.-H. Cho M.-L. IL-1-IL-17 signaling axis contributes to fibrosis and inflammation in two different murine models of systemic sclerosis.Front Immunol. 2018; 9: 1611Crossref PubMed Scopus (53) Google ScholarHowever, some evidence indicates that IL-1β can exert both synergistic and antagonist effects on transforming growth factor-β function, epithelial-to-mesenchymal transformation, and collagen deposition.47Masola V. Carraro A. Granata S. Signorini L. Bellin G. Violi P. Lupo A. Tedeschi U. Onisto M. Gambaro G. Zaza G. In vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells.J Translational Med. 2019; 17: 12Google Scholar,48Mia M.M. Boersema M. Bank R.A. Interleukin-1β attenuates myofibroblast formation and extracellular matrix production in dermal and lung fibroblasts exposed to transforming growth factor-β1.PLoS One. 2014; 9: e91559Crossref PubMed Scopus (67) Google Scholar Lung fibroblasts, but not dermal fibroblasts, display a reduced transforming growth factor-β–mediated production of collagen when treated with IL-1β and IL-1, produced by the airway epithelium, which similarly modulates fibroblast activity.49Osei E.T. Mostaço-Guidolin L.B. Hsieh A. Warner S.M. Al-Fouadi M. Wang M. Cole D.J. Maksym G.N. Hallstrand T.S. Timens W. Brandsma C.-A. Heijink I.H. Hackett T.-L. Epithelial-interleukin-1 inhibits collagen formation by airway fibroblasts: implications for asthma.Sci Rep. 2020; 10: 8721Crossref PubMed Scopus (12) Google Scholar It is possible that IL-1 family cytokines—products of NLRP3 activation—not only participate as mediators of inflammation, but also act as regulators of their intrinsic network, with cell, and organ, specificity. This mechanism could promote balanced inflammatory responses to a wide range of stressors able to activate NLRP3.NLRP3 in IPFThe development of an animal model of a disease with idiopathic (ie, unknown) etiology is at best challenging. Intratracheal instillation of bleomycin (BLM) is the most commonly used animal model of IPF, which, however, remains suboptimal because of the unknown origin of IPF.50Jenkins R.G. Moore B.B. Chambers R.C. Eickelberg O. Königshoff M. Kolb M. Laurent G.J. Nanthakumar C.B. Olman M.A. Pardo A. Selman M. Sheppard D. Sime P.J. Tager A.M. Tatler A.L. Thannickal V.J. White E.S. ATSAoR Cell and B MolecularAn official American Thoracic Society workshop report: use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis.Am J Respir Cell Mol Biol. 2017; 56: 667-679Crossref PubMed Scopus (153) Google Scholar BLM induces DNA damage via oxidative stress, and inflammation, repair, and fibrotic responses are mediated by IL-1β and the IL-R1/myeloid differentiation primary response gene 88 signaling pathway.51Gasse P. Mary C. Guenon I. Noulin N. Charron S. Schnyder-Candrian S. Schnyder B. Akira S. Quesniaux V.F. Lagente V. Ryffel B. Couillin I. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice.J Clin Invest. 2007; 117: 3786-3799PubMed Google Scholar NLRP3−/− mice display much lower levels of NLRP3 activation, IL-1β production, and fibrosis compared with wild-type animals.52Gasse P. Riteau N. Charron S. Girre S. Fick L. Pétrilli V. Tschopp J. Lagente V. Quesniaux V.F. Ryffel B. Couillin I. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis.Am J Respir Crit Care Med. 2009; 179: 903-913Crossref PubMed Scopus (321) Google Scholar The activation of the inflammasome NLRP3 in IPF has been ascribed to multiple interrelated as well as distinct signaling mechanisms.Extracellular ATPPurine nucleotides and nucleosides are critical structures for eukaryotic systems. ATP represents the fundamental energy exchange utilized by cells, but when released in the extracellular space in response to cell injury, acts as damage-associated molecular patterns and, depending on metabolic processing and receptor binding, exerts proinflammatory or anti-inflammatory effects.The BALF of IPF patients displays increased levels of extracellular ATP and UDP, which increases during disease flare-ups.53Müller T. Fay S. Vieira R.P. Karmouty-Quintana H. Cicko S. Ayata K. Zissel G. Goldmann T. Lungarella G. Ferrari D. Di Virgilio F. Robaye B. Boeynaems J.M. Blackburn M.R. Idzko M. The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease.Oncotarget. 2017; 8: 35962-35972Google Scholar,54Riteau N. Gasse P. Fauconnier L. Gombault A. Couegnat M. Fick L. Kanellopoulos J. Quesniaux V.F. Marchand-Adam S. Crestani B. Ryffel B. Couillin I. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis.Am J Respir Crit Care Med. 2010; 182: 774-783Crossref PubMed Scopus (300) Google Scholar The expression of the purinergic receptor, P2Y2, is increased on macrophages and neutrophils, whereas alveolar epithelial cells display mostly P2Y6 receptors.55Müller T. Fay S. Vieira R.P. Karmouty-Quintana H. Cicko S. Ayata C.K. Zissel G. Goldmann T. Lungarella G. Ferrari D. Di Virgilio F. Robaye B. Boeynaems J.-M. Lazarowski E.R. Blackburn M.R. Idzko M. P2Y6 receptor activation promotes inflammation and tissue remodeling in pulmonary fibrosis.Front Immunol. 2017; 8: 1028Crossref PubMed Scopus (19) Google Scholar Accordingly, high levels of extracellular ATP exist in BLM-instilled fibrotic mice,54Riteau N. Gasse P. Fauconnier L. Gombault A. Couegnat M. Fick L. Kanellopoulos J. Quesniaux V.F. Marchand-Adam S. Crestani B. Ryffel B. Couillin I. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis.Am J Respir Crit Care Med. 2010; 182: 774-783Crossref PubMed Scopus (300) Google Scholar and genetic exclusion of either P2Y2 or P2Y6 genes resulted in mice expressing lower inflammation and white blood cell recruitment. In IPF, extracellular ATP is probably released as a result of continuous micro-injuries, airway remodeling, and disorganized and excessive angiogenesis with copious extracellular matrix deposition and mesenchymal transition. Extracellular ATPs a
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