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NLRP3 İnflamazom Aktivasyon ve Düzenleme Mekanizmalarına Genel Bir Bakış

Yıl 2022, Cilt: 31 Sayı: 1, 52 - 59, 31.03.2022

Dilek Şaker Sait Polat

https://doi.org/10.17827/aktd.1008686

Öz

Doğal bağışıklık sistemi, vücuda giren patojenlere karşı konakçı savunmasında hayati önem taşır. Doğal bağışıklık sisteminin bir bileşeni olan NLRP3 (NACHT-, LRR- ve pirin alanı içeren 3) inflamazom, multimerik bir protein kompleksidir. İnflamazom aktivasyonu klasik enflamatuvar cevaplardan farklı olarak başlayan ve gelişen bir süreçtir. NLRP3 inflamazom aktivasyonunun oluşması için DAMP'ler (Hasarlanma ile ilişkili moleküler modeller) ve PAMP'ler (Patojenle ilişkili moleküler modeller) gibi çeşitli tehlike sinyallerinin olması gerekir. Bu uyaranlara yanıt olarak, kaspaz-1 aktive olur. Aktif kaspaz-1 de, IL-1β (interlökin-1β) ve IL-18 (interlökin-18) sitokinlerinin öncül halde bulunan formlarını proteolitik olarak böler ve aktif hale getirir. Böylece IL-1β ve IL-18 aracılı enflamatuvar yanıtlar aktive olur. NLPR3 aktivasyonu önemli bir bağışıklık cevabı olmasına rağmen aşırı aktivasyonu enflamatuvar hastalıklara ve hücre ölümüne neden olabilmektedir. Bu nedenden dolayı, NLRP3 inflamazomunun regülasyonu ve inhibisyonu otoenflamatuvar hastalıklar için umut verici bir tedavi yaklaşımı olabilir. Bu derlemede, NLRP3 inflamazom aktivasyon mekanizmaları hakkındaki mevcut anlayışın yanı sıra standart olmayan ve alternatif inflamazom yolaklarındaki son gelişmeler sunulmuştur.

Anahtar Kelimeler

Enflamasyon NLRP3 İnflamazom Otoimmün Hastalıklar

Kaynakça

  • Referans 1. Kesikli SA, Güç D. Steril İnflamasyon ve İnflamazom. ANKEM Derg. 2011;25(Ek 2):102-9.
  • Referans 2. Sharma D, Kanneganti TD. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J. Cell Biol. 2016;213:617–29.
  • Referans 3. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci. 2019;20:3328.
  • Referans 4. Schroder K, Tschopp J. The Inflammasomes. Cell. 2010;140:821–32.
  • Referans 5. Shao B, Xu Z, Han B, Su D, Liu C. NLRP3 inflammasome and its inhibitors: a review. Frontiers in Pharmacolog. 2015;6:262.
  • Referans 6. Trdizin. Available from: https://app.trdizin.gov.tr/dokuman-goruntule?ext=pdf&path=CrnWZGRsXTjRjLjWxD978OSUAL2jXitizhVYmCxNvH4Z8Ahs_kDHkpOxOpWgszYwDyLztUwSuCHva_2PxJac6LjQwtnm8RiZLCI2oA_RET6abSR9cp62ynnLp3sfPyY70W8607s7mQZM810EOcuowow_Bq5symYzpbJlJABjs7JZpI13HG1vGn4Li84WOfSzdJrsxZxRjlCPJ9sZtOkSBOw_3uNLnlGCpPJDhfrBbIk=&contentType=application/pdf. Accessed: 12 October 2021.
  • Referans 7. He Y, Hara H, Nunez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012–21.
  • Referans 8. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nature Reviews. 2018;17:588-606.
  • Referans 9. Şahin C, Arıcıoğlu F. Depresyon ve Sitokin Hipotezinde Yeni Bir Boyut: ‘NLRP3 İnflamazomu’. MÜSBED. 2013;3(2):65-8.
  • Referans 10. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES. The pyroptosome: A supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14:1590–604.
  • Referans 11. Arıöz Bİ. Melatonin´in Mikroglial Hücrelerde İnflamazom Aktivasyonuna Etkisi (Yüksek Lisans Tezi). İzmir. Dokuz Eylül Üniversitesi. 2017.
  • Referans 12. Kim N, Kim H, Lee J, Jo S, Won H, Lee G, et al. Juglone Suppresses LPS-induced Inflammatory Responses and NLRP3 Activation in Macrophages. Molecules. 2020;25;3104.
  • Referans 13. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting Edge: NF-kB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression. J. Immunol. 2009;183:787-91.
  • Referans 14. Gurung P, Anand PK, Malireddi RKS, Walle LV, Opdenbosch NV, Dillon CP, et al. FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes. J. Immunol. 2014;192:1835–46.
  • Referans 15. Allam R, Lawlor KE, Yu ECW, Mildenhall AL, Moujalled DM, Lewis RS, et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 2014;15:982–90.
  • Referans 16. Lemmers B, Salmena L, Bidere N, Su H, Matysiak-Zablocki E, Murakami K, et al. Essential Role for Caspase-8 in Toll-like Receptors and NF-kB Signaling. J. Biol. Chem. 2007;282:7416–23.
  • Referans 17. Kim SJ, Cha JY, Kang HS, Lee JH, Lee JY, Park JH, et al. Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages. BMB Rep. 2016; 49:276–81.
  • Referans 18. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death and Differentiation. 2007; 14:1583–9.
  • Referans 19. Franchi L, Kanneganti T, Dubyak GR, Nunez G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. Journal of Biological Chemistry. 2007;282:18810–8.
  • Referans 20. Munoz-Planillo R, Kuffa P, Martínez-Colon G, Smith BL, Rajendiran TM, Nunez G, et al. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.
  • Referans 21. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012;109:11282–7.
  • Referans 22. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012; 492:123–7.
  • Referans 23. Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 2011;286:35–41.
  • Referans 24. Verhoef PA, Kertesy SB, Lundberg K, Kahlenberg JM, Dubyak GR. Inhibitory e ects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor. J. Immunol. Baltim. Md 1950. 2005;175:7623–34.
  • Referans 25. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.
  • Referans 26. Nakahira K, Haspel JA, Rathinam VAK, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 2011:12;222–30.
  • Referans 27. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis. Immunity .2012,36,401–14.
  • Referans 28. Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin X, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560:198–203.
  • Referans 29. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 2008;9:847–56.
  • Referans 30. Weber K, Schilling JD. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J. Biol. Chem. 2014;289:9158–71.
  • Referans 31. Kayagaki N, Warming S, Lamkanfi M, Walle LV, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21.
  • Referans 32. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014;514:187–92.
  • Referans 33. Evavold CL. Ruan J, Tan T, Xia S, Wu H, Kagan JC. The pore-forming protein gasdermin D regulates interleukin‑1 secretion from living macrophages. Immunity. 2018;48:35–44.
  • Referans 34. Zanoni I, Tan Y, Di Gioia M, Springstead JR. Kagan JC. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity. 2017;47:697–709.
  • Referans 35. He Y, Franchi, Gabriel Nunez. TLR agonists stimulate Nlrp3-dependent IL-1beta production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol. 2013; 190:334–9.
  • Referans 36. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.
  • Referans 37. Chow MT, Sceneay J, Paget C, Wong CSF, Duret H, Tschopp J, et al. NLRP3 suppresses NK cell mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 2012;72:5721–32.
  • Referans 38. van Deventer HW, Burgents JE, Wu QP, Woodford RT, Brickey WJ, Allen IC, et al. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res. 2010;70:10161-9.
  • Referans 39. Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. The inflammasomes and autoinflammatory syndromes. Annu. Rev. Pathol. 2015;10:395–424.

An Overview of NLRP3 Inflammasome Activation and Regulation Mechanisms

Yıl 2022, Cilt: 31 Sayı: 1, 52 - 59, 31.03.2022

Dilek Şaker Sait Polat

https://doi.org/10.17827/aktd.1008686

Öz

The innate immune system is vital in host defense against pathogens entering the body. The NLRP3 (NACHT-, LRR- and Pyrin Domain Containing 3) inflammasome, a component of the innate immune system, is a multimeric protein complex. Inflammasome activation is a process that starts and improves differently from classical inflammatory responses. In order to induce inflammasome activation, there must be a danger signal such as DAMP (Damage-Associated Molecular Pattern) or PAMP (Pathogen-Associated Molecular Pattern) detected. In response to these stimuli, caspase-1 is activated. This in turn leads to cleavage and maturation of potent pro-inflammatory cytokines, IL-1β (interleukin-1β) and IL-18 (interleukin-18) by mature caspase-1. Thus, inflammatory responses mediated by IL-1β and IL-18 are activated. Although NLPR3 activation is an important immune response, its overactivation can cause inflammatory disorders and cell death. For this reason, regulation and inhibition of the NLRP3 inflammasome may be a promising treatment approach for these autoinflammatory diseases. In this review presents the current understanding of the mechanisms of NLRP3 inflammasome activation, as well as recent advances in the non-canonical and alternative inflammasome pathways.

Anahtar Kelimeler

Inflammation NLRP3 inflammasome Autoinflammatory diseases

Kaynakça

  • Referans 1. Kesikli SA, Güç D. Steril İnflamasyon ve İnflamazom. ANKEM Derg. 2011;25(Ek 2):102-9.
  • Referans 2. Sharma D, Kanneganti TD. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J. Cell Biol. 2016;213:617–29.
  • Referans 3. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci. 2019;20:3328.
  • Referans 4. Schroder K, Tschopp J. The Inflammasomes. Cell. 2010;140:821–32.
  • Referans 5. Shao B, Xu Z, Han B, Su D, Liu C. NLRP3 inflammasome and its inhibitors: a review. Frontiers in Pharmacolog. 2015;6:262.
  • Referans 6. Trdizin. Available from: https://app.trdizin.gov.tr/dokuman-goruntule?ext=pdf&path=CrnWZGRsXTjRjLjWxD978OSUAL2jXitizhVYmCxNvH4Z8Ahs_kDHkpOxOpWgszYwDyLztUwSuCHva_2PxJac6LjQwtnm8RiZLCI2oA_RET6abSR9cp62ynnLp3sfPyY70W8607s7mQZM810EOcuowow_Bq5symYzpbJlJABjs7JZpI13HG1vGn4Li84WOfSzdJrsxZxRjlCPJ9sZtOkSBOw_3uNLnlGCpPJDhfrBbIk=&contentType=application/pdf. Accessed: 12 October 2021.
  • Referans 7. He Y, Hara H, Nunez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012–21.
  • Referans 8. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nature Reviews. 2018;17:588-606.
  • Referans 9. Şahin C, Arıcıoğlu F. Depresyon ve Sitokin Hipotezinde Yeni Bir Boyut: ‘NLRP3 İnflamazomu’. MÜSBED. 2013;3(2):65-8.
  • Referans 10. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES. The pyroptosome: A supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14:1590–604.
  • Referans 11. Arıöz Bİ. Melatonin´in Mikroglial Hücrelerde İnflamazom Aktivasyonuna Etkisi (Yüksek Lisans Tezi). İzmir. Dokuz Eylül Üniversitesi. 2017.
  • Referans 12. Kim N, Kim H, Lee J, Jo S, Won H, Lee G, et al. Juglone Suppresses LPS-induced Inflammatory Responses and NLRP3 Activation in Macrophages. Molecules. 2020;25;3104.
  • Referans 13. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting Edge: NF-kB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression. J. Immunol. 2009;183:787-91.
  • Referans 14. Gurung P, Anand PK, Malireddi RKS, Walle LV, Opdenbosch NV, Dillon CP, et al. FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes. J. Immunol. 2014;192:1835–46.
  • Referans 15. Allam R, Lawlor KE, Yu ECW, Mildenhall AL, Moujalled DM, Lewis RS, et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 2014;15:982–90.
  • Referans 16. Lemmers B, Salmena L, Bidere N, Su H, Matysiak-Zablocki E, Murakami K, et al. Essential Role for Caspase-8 in Toll-like Receptors and NF-kB Signaling. J. Biol. Chem. 2007;282:7416–23.
  • Referans 17. Kim SJ, Cha JY, Kang HS, Lee JH, Lee JY, Park JH, et al. Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages. BMB Rep. 2016; 49:276–81.
  • Referans 18. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death and Differentiation. 2007; 14:1583–9.
  • Referans 19. Franchi L, Kanneganti T, Dubyak GR, Nunez G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. Journal of Biological Chemistry. 2007;282:18810–8.
  • Referans 20. Munoz-Planillo R, Kuffa P, Martínez-Colon G, Smith BL, Rajendiran TM, Nunez G, et al. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.
  • Referans 21. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012;109:11282–7.
  • Referans 22. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012; 492:123–7.
  • Referans 23. Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 2011;286:35–41.
  • Referans 24. Verhoef PA, Kertesy SB, Lundberg K, Kahlenberg JM, Dubyak GR. Inhibitory e ects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor. J. Immunol. Baltim. Md 1950. 2005;175:7623–34.
  • Referans 25. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.
  • Referans 26. Nakahira K, Haspel JA, Rathinam VAK, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 2011:12;222–30.
  • Referans 27. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis. Immunity .2012,36,401–14.
  • Referans 28. Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin X, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560:198–203.
  • Referans 29. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 2008;9:847–56.
  • Referans 30. Weber K, Schilling JD. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J. Biol. Chem. 2014;289:9158–71.
  • Referans 31. Kayagaki N, Warming S, Lamkanfi M, Walle LV, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21.
  • Referans 32. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014;514:187–92.
  • Referans 33. Evavold CL. Ruan J, Tan T, Xia S, Wu H, Kagan JC. The pore-forming protein gasdermin D regulates interleukin‑1 secretion from living macrophages. Immunity. 2018;48:35–44.
  • Referans 34. Zanoni I, Tan Y, Di Gioia M, Springstead JR. Kagan JC. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity. 2017;47:697–709.
  • Referans 35. He Y, Franchi, Gabriel Nunez. TLR agonists stimulate Nlrp3-dependent IL-1beta production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol. 2013; 190:334–9.
  • Referans 36. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.
  • Referans 37. Chow MT, Sceneay J, Paget C, Wong CSF, Duret H, Tschopp J, et al. NLRP3 suppresses NK cell mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 2012;72:5721–32.
  • Referans 38. van Deventer HW, Burgents JE, Wu QP, Woodford RT, Brickey WJ, Allen IC, et al. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res. 2010;70:10161-9.
  • Referans 39. Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. The inflammasomes and autoinflammatory syndromes. Annu. Rev. Pathol. 2015;10:395–424.
Toplam 39 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Sağlık Kurumları Yönetimi
Bölüm Derleme
Yazarlar

Dilek Şaker 0000-0002-5055-4226

Sait Polat 0000-0003-1646-8831

Yayımlanma Tarihi 31 Mart 2022
Kabul Tarihi 12 Kasım 2021
Yayımlandığı Sayı Yıl 2022 Cilt: 31 Sayı: 1

Kaynak Göster

AMA Şaker D, Polat S. NLRP3 İnflamazom Aktivasyon ve Düzenleme Mekanizmalarına Genel Bir Bakış. aktd. Mart 2022;31(1):52-59. doi:10.17827/aktd.1008686
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