Skip to main content
Erschienen in: Inflammation Research 3/2012

01.03.2012 | Original Research Paper

The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis

Erschienen in: Inflammation Research | Ausgabe 3/2012

Einloggen, um Zugang zu erhalten

Abstract

Objective

The inflammasome complex involving caspase-1 and nucleotide-binding domain, leucine-rich repeat containing protein (NLRP)3, also known as NALP3 or cryopyrin is important for host responses to microbial pathogens and several autoinflammatory diseases. We investigated the extent to which NLRP3 and caspase-1 control ocular interleukin (IL)-1β production and severity of uveitis (intraocular inflammatory disease) in an established, acute inflammatory uveitis model, endotoxin-induced uveitis (EIU).

Methods

Expression of NLRP3, its adaptor molecule ASC, also known as PYCARD (PYD and CARD domain containing), and caspase-1 were examined by immunoblotting. IL-1β production was measured by enzyme-linked immunosorbent assay (ELISA). Using knockout mice, roles for caspase-1 and NLRP3 were examined in uveitis induced by intraocular injection of Escherichia coli lipopolysaccharide (LPS).

Results

NLRP3, ASC, and caspase-1 proteins are constitutively expressed in eye tissue. During EIU, IL-1β protein production increases; this requires the presence of both caspase-1 and NLRP3. However, severity of EIU is not altered by deficiency in either caspase-1 or NLRP3, as assessed by both intravital microscopy and histology.

Conclusions

These data identify the importance of the NLRP3 inflammasome for IL-1β production in the eye, yet indicate that its participation in EIU is nonessential.
Literatur
1.
Zurück zum Zitat Martinon F, Mayor A, Tschopp J. The Inflammasomes: Guardians of the Body. Annu Rev Immunol. 2009;27:229–65.PubMedCrossRef Martinon F, Mayor A, Tschopp J. The Inflammasomes: Guardians of the Body. Annu Rev Immunol. 2009;27:229–65.PubMedCrossRef
2.
Zurück zum Zitat Brodsky IE, Monack D. NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens. Semin Immunol. 2009;21:199–207.PubMedCrossRef Brodsky IE, Monack D. NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens. Semin Immunol. 2009;21:199–207.PubMedCrossRef
3.
Zurück zum Zitat Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.PubMedCrossRef Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.PubMedCrossRef
4.
Zurück zum Zitat Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141–9.PubMedCrossRef Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141–9.PubMedCrossRef
5.
Zurück zum Zitat Chitkara P, Stojanov S, Kastner DL. The hereditary autoinflammatory syndromes. Pediatr Infect Dis. 2007;26:353–4.CrossRef Chitkara P, Stojanov S, Kastner DL. The hereditary autoinflammatory syndromes. Pediatr Infect Dis. 2007;26:353–4.CrossRef
6.
Zurück zum Zitat Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720–32.PubMedCrossRef Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720–32.PubMedCrossRef
7.
Zurück zum Zitat McGarry F, Neilly J, Anderson N, Sturrock R, Field M. A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis. Rheumatology. 2001;40:1359–64.PubMedCrossRef McGarry F, Neilly J, Anderson N, Sturrock R, Field M. A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis. Rheumatology. 2001;40:1359–64.PubMedCrossRef
8.
Zurück zum Zitat Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6:232–41.PubMedCrossRef Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6:232–41.PubMedCrossRef
9.
Zurück zum Zitat Djouadi K, Nedelec B, Tamouza R, Genin E, Ramasawmy R, Charron D, et al. Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies. Cytokine. 2001;13:98–103.PubMedCrossRef Djouadi K, Nedelec B, Tamouza R, Genin E, Ramasawmy R, Charron D, et al. Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies. Cytokine. 2001;13:98–103.PubMedCrossRef
10.
Zurück zum Zitat Maksymowych WP, Reeve JP, Reveille JD, Akey JM, Buenviaje H, O’Brien L, et al. High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum. 2003;48:2011–8.PubMedCrossRef Maksymowych WP, Reeve JP, Reveille JD, Akey JM, Buenviaje H, O’Brien L, et al. High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum. 2003;48:2011–8.PubMedCrossRef
11.
Zurück zum Zitat Hutyrova B, Pantelidis P, Drabek J, Zurkova M, Kolek V, Lenhart K, et al. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2002;165:148–51.PubMed Hutyrova B, Pantelidis P, Drabek J, Zurkova M, Kolek V, Lenhart K, et al. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2002;165:148–51.PubMed
12.
Zurück zum Zitat Coskun M, Bacanli A, Sallakci N, Alpsoy E, Yavuzer U, Yegin O. Specific interleukin-1 gene polymorphisms in Turkish patients with Behçet’s disease. Exp Dermatol. 2005;14:124–9.PubMedCrossRef Coskun M, Bacanli A, Sallakci N, Alpsoy E, Yavuzer U, Yegin O. Specific interleukin-1 gene polymorphisms in Turkish patients with Behçet’s disease. Exp Dermatol. 2005;14:124–9.PubMedCrossRef
13.
Zurück zum Zitat Karasneh J, Hajeer AH, Barrett J, Ollier WE, Thornhill M, Gul A. Association of specific interleukin 1 gene cluster polymorphisms with increased susceptibility for Behcet’s disease. Rheumatology. 2003;42:860–4.PubMedCrossRef Karasneh J, Hajeer AH, Barrett J, Ollier WE, Thornhill M, Gul A. Association of specific interleukin 1 gene cluster polymorphisms with increased susceptibility for Behcet’s disease. Rheumatology. 2003;42:860–4.PubMedCrossRef
14.
Zurück zum Zitat Gonzalez-Benitez JF, Juarez-Verdayes MA, Rodriguez-Martinez S, Cancino-Diaz ME, Garcia-Vasquez F, Cancino-Diaz JC. The NALP3/Cryopyrin-inflammasome complex is expressed in LPS-induced ocular inflammation. Mediators Inflamm 2008;2008:7. Gonzalez-Benitez JF, Juarez-Verdayes MA, Rodriguez-Martinez S, Cancino-Diaz ME, Garcia-Vasquez F, Cancino-Diaz JC. The NALP3/Cryopyrin-inflammasome complex is expressed in LPS-induced ocular inflammation. Mediators Inflamm 2008;2008:7.
15.
Zurück zum Zitat Rosenbaum JT, McDevitt HO, Guss RB, Egbert PR. Endotoxin-induced uveitis in rats as a model for human disease. Nature. 1980;286:611–3.PubMedCrossRef Rosenbaum JT, McDevitt HO, Guss RB, Egbert PR. Endotoxin-induced uveitis in rats as a model for human disease. Nature. 1980;286:611–3.PubMedCrossRef
16.
Zurück zum Zitat Becker MD, Nobiling R, Planck SR, Rosenbaum JT. Digital video-imaging of leukocyte migration in the iris: intravital microscopy in a physiological model during the onset of endotoxin-induced uveitis. J Immunol Methods. 2000;240:23–37.PubMedCrossRef Becker MD, Nobiling R, Planck SR, Rosenbaum JT. Digital video-imaging of leukocyte migration in the iris: intravital microscopy in a physiological model during the onset of endotoxin-induced uveitis. J Immunol Methods. 2000;240:23–37.PubMedCrossRef
17.
Zurück zum Zitat Rosenzweig HL, Martin TM, Jann MM, Planck SR, Davey MP, Kobayashi K, et al. NOD2, the gene responsible for familial granulomatous uveitis, is essential in a mouse model of muramyl dipeptide-induced uveitis. Invest Ophthalmol Vis Sci. 2008;49:1518–24.PubMedCrossRef Rosenzweig HL, Martin TM, Jann MM, Planck SR, Davey MP, Kobayashi K, et al. NOD2, the gene responsible for familial granulomatous uveitis, is essential in a mouse model of muramyl dipeptide-induced uveitis. Invest Ophthalmol Vis Sci. 2008;49:1518–24.PubMedCrossRef
18.
Zurück zum Zitat Rosenzweig H, Galster K, Planck S, Rosenbaum J. NOD1 expression in the eye and functional contribution to IL-1{beta} dependent ocular inflammation in mice. Invest Ophthalmol Vis Sci. 2009;50:1746–53.PubMedCrossRef Rosenzweig H, Galster K, Planck S, Rosenbaum J. NOD1 expression in the eye and functional contribution to IL-1{beta} dependent ocular inflammation in mice. Invest Ophthalmol Vis Sci. 2009;50:1746–53.PubMedCrossRef
19.
Zurück zum Zitat Yu HB, Finlay BB. The caspase-1 inflammasome: a pilot of innate immune responses. Cell Host Microbe. 2008;11:198–208.CrossRef Yu HB, Finlay BB. The caspase-1 inflammasome: a pilot of innate immune responses. Cell Host Microbe. 2008;11:198–208.CrossRef
20.
Zurück zum Zitat Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kosturan MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992;356:768–74.PubMedCrossRef Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kosturan MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992;356:768–74.PubMedCrossRef
21.
Zurück zum Zitat Willingham SB, Allen IC, Bergstralh DT, Brickey WJ, Huang MT, Taxman DJ, et al. NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. J Immunol. 2009;183:2008–15.PubMedCrossRef Willingham SB, Allen IC, Bergstralh DT, Brickey WJ, Huang MT, Taxman DJ, et al. NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. J Immunol. 2009;183:2008–15.PubMedCrossRef
22.
Zurück zum Zitat Reimer T, Shaw MH, Franchi L, Coban C, Ishii KJ, Akira S, et al. Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. Eur J Immunol. 2010;40:764–9.PubMedCrossRef Reimer T, Shaw MH, Franchi L, Coban C, Ishii KJ, Akira S, et al. Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. Eur J Immunol. 2010;40:764–9.PubMedCrossRef
23.
Zurück zum Zitat Becker MD, O’Rourke LM, Blackman WS, Planck SR, Rosenbaum JT. Reduced leukocyte migration, but normal rolling and arrest, in interleukin-8 receptor homologue knockout mice. Invest Ophthalmol Vis Sci. 2000;41:1812–7.PubMed Becker MD, O’Rourke LM, Blackman WS, Planck SR, Rosenbaum JT. Reduced leukocyte migration, but normal rolling and arrest, in interleukin-8 receptor homologue knockout mice. Invest Ophthalmol Vis Sci. 2000;41:1812–7.PubMed
24.
Zurück zum Zitat Tuaillon N, Shen DF, Berger RB, Lu B, Rollins BJ, Chan CC. MCP-1 expression in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2002;43:1493–8.PubMed Tuaillon N, Shen DF, Berger RB, Lu B, Rollins BJ, Chan CC. MCP-1 expression in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2002;43:1493–8.PubMed
25.
Zurück zum Zitat Whitcup SM, DeBarge R, Caspi RR, Harning R, Nussenblatt RB, Chan C–C. Monoclonal antibodies against ICAM-1 (CD54) and LFA-1 (CD11a/CD18) inhibit experimental autoimmune uveitis. Clin Immunol Immunopathol. 1993;67:143–50.PubMedCrossRef Whitcup SM, DeBarge R, Caspi RR, Harning R, Nussenblatt RB, Chan C–C. Monoclonal antibodies against ICAM-1 (CD54) and LFA-1 (CD11a/CD18) inhibit experimental autoimmune uveitis. Clin Immunol Immunopathol. 1993;67:143–50.PubMedCrossRef
26.
Zurück zum Zitat Rosenbaum JT, Han YB, Park JM, Kennedy M, Planck SR. TNFα is not a major mediator of endotoxin-induced uveitis: studies in cytokine receptor deficient mice. J Rheumatol. 1998;25:2408–516.PubMed Rosenbaum JT, Han YB, Park JM, Kennedy M, Planck SR. TNFα is not a major mediator of endotoxin-induced uveitis: studies in cytokine receptor deficient mice. J Rheumatol. 1998;25:2408–516.PubMed
27.
Zurück zum Zitat Rosenzweig HL, Martin TM, Planck SR, Galster K, Jann MM, Davey MP, et al. Activation of NOD2 in vivo induces IL-1 beta production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling. J Leukoc Biol. 2008;84:529–36.PubMedCrossRef Rosenzweig HL, Martin TM, Planck SR, Galster K, Jann MM, Davey MP, et al. Activation of NOD2 in vivo induces IL-1 beta production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling. J Leukoc Biol. 2008;84:529–36.PubMedCrossRef
28.
Zurück zum Zitat Arostegui J, Arnal C, Merino R, Modesto C, Antonia Caballo J, Moreno P, et al. NON2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum. 2007;56:3805–13.PubMedCrossRef Arostegui J, Arnal C, Merino R, Modesto C, Antonia Caballo J, Moreno P, et al. NON2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum. 2007;56:3805–13.PubMedCrossRef
29.
Zurück zum Zitat Martin TM, Zhang Z, Kurz P, Rose CD, Chen H, Lu H, et al. The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum. 2009;60:611–8.PubMedCrossRef Martin TM, Zhang Z, Kurz P, Rose CD, Chen H, Lu H, et al. The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum. 2009;60:611–8.PubMedCrossRef
30.
Zurück zum Zitat Brito BE, O’Rourke L, Pan Y, Anglin J, Planck SR, Rosenbaum JT. IL-1 and TNF receptor deficient mice show decreased inflammation in an immune complex model of uveitis. Invest Ophthalmol Vis Sci. 1999;40:2583–9.PubMed Brito BE, O’Rourke L, Pan Y, Anglin J, Planck SR, Rosenbaum JT. IL-1 and TNF receptor deficient mice show decreased inflammation in an immune complex model of uveitis. Invest Ophthalmol Vis Sci. 1999;40:2583–9.PubMed
31.
Zurück zum Zitat Su SB, Silver PB, Grajewski RS, Agarwal RK, Tang J, Chan CC, et al. Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity. J Immunol. 2005;175:6303–10.PubMed Su SB, Silver PB, Grajewski RS, Agarwal RK, Tang J, Chan CC, et al. Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity. J Immunol. 2005;175:6303–10.PubMed
32.
Zurück zum Zitat Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS-S, et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1á converting enzyme. Science. 1995;267:2000–3.PubMedCrossRef Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS-S, et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1á converting enzyme. Science. 1995;267:2000–3.PubMedCrossRef
33.
Zurück zum Zitat Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997;386:619–23.PubMedCrossRef Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997;386:619–23.PubMedCrossRef
34.
Zurück zum Zitat Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell. 1995;80:401–11.PubMedCrossRef Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell. 1995;80:401–11.PubMedCrossRef
35.
Zurück zum Zitat Shen DF, Buggage RR, Engl HC, Chan CC. Cytokine gene expression in different strains of mice with endotoxin-induced uveitis (EIU). Ocul Immunol Inflamm. 2000;8:221–5.PubMedCrossRef Shen DF, Buggage RR, Engl HC, Chan CC. Cytokine gene expression in different strains of mice with endotoxin-induced uveitis (EIU). Ocul Immunol Inflamm. 2000;8:221–5.PubMedCrossRef
36.
Zurück zum Zitat Imai H, Ohta K, Yoshida A, Suzuki S, Hashizume K, Usami S, et al. {micro}-Crystallin, new candidate protein in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2010;51:3554–9.PubMedCrossRef Imai H, Ohta K, Yoshida A, Suzuki S, Hashizume K, Usami S, et al. {micro}-Crystallin, new candidate protein in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2010;51:3554–9.PubMedCrossRef
37.
Zurück zum Zitat Netea MG, Nold-Petry CA, Nold MF, Joosten LA, Optiz B, van der Meer JH, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood. 2009;113:2324–35.PubMedCrossRef Netea MG, Nold-Petry CA, Nold MF, Joosten LA, Optiz B, van der Meer JH, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood. 2009;113:2324–35.PubMedCrossRef
38.
Zurück zum Zitat Piccini A, Carta S, Tassi S, Lasiglie D, Fossati G, Rubartelli A. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc Natl Acad Sci USA. 2008;105:8067–72.PubMedCrossRef Piccini A, Carta S, Tassi S, Lasiglie D, Fossati G, Rubartelli A. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc Natl Acad Sci USA. 2008;105:8067–72.PubMedCrossRef
39.
Zurück zum Zitat Teoh SC, Sharma S, Hogan A, Lee R, Ramanan AV, Dick AD. Tailoring biological treatment: anakinra treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol. 2007;91:263–4.PubMedCrossRef Teoh SC, Sharma S, Hogan A, Lee R, Ramanan AV, Dick AD. Tailoring biological treatment: anakinra treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol. 2007;91:263–4.PubMedCrossRef
40.
Zurück zum Zitat Deal watch: XOMA, Servier to develop anti-IL-1β antibody for inflammatory diseases. Nat Rev Drug Discov 2011;10:166. Deal watch: XOMA, Servier to develop anti-IL-1β antibody for inflammatory diseases. Nat Rev Drug Discov 2011;10:166.
Metadaten
Titel
The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis
Publikationsdatum
01.03.2012
Erschienen in
Inflammation Research / Ausgabe 3/2012
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-011-0404-8

Weitere Artikel der Ausgabe 3/2012

Inflammation Research 3/2012 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.