Regulación del inflamasoma NLRP3: bioquímica y más allá de ella
DOI:
https://doi.org/10.17533/udea.iatreia.v28n2a07Palabras clave:
caspasa-1, epigenética, inflamasoma, NLRP3, regulaciónResumen
La inmunidad innata responde a la infección y al daño tisular activando una plataforma molecular denominada inflamasoma. En las investigaciones clínicas con humanos, se han descrito cuatro clases de inflamasomas relacionados con procesos inflamatorios: NLRP1, NLRC4, NLRP3 y AIM-2. De ellos, NLRP3 es el mejor estudiado. Los inflamasomas tienen como finalidad común el procesamiento y activación de la caspasa-1, enzima responsable de la maduración de pro-IL-1β y pro-IL-18. El control génico y la regulación bioquímica de esta plataforma son fundamentales para evitar el desarrollo de enfermedades inmunológicas, metabólicas y neurológicas. Algunos de los mecanismos más importantes en la modulación de la actividad del inflamasoma son: los polimorfismos en los genes codificadores de las proteínas del inflamasoma, la ubiquitinación, la regulación redox, la concentración de ATP y la señalización paracrina mediante factores de transcripción e interleucinas. Existe, además, otro tipo de regulación que se ejerce por mecanismos epigenéticos como la metilación y la expresión de micro-ARN. En conjunto, estos mecanismos son indispensables para la expresión coordinada y el funcionamiento correcto de estas plataformas moleculares ante un determinado patógeno o daño celular. Las investigaciones sobre los diversos componentes de los inflamasomas y su inhibición controlada están esclareciendo aspectos que permitirán controlar enfermedades asociadas con estos complejos moleculares.
Descargas
Citas
(1.) Chen S, Sun B. Negative regulation of NLRP3 inflammasome signaling. Protein Cell. 2013 Apr;4(4):251–8.
(2.) Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002 Aug;10(2):417–26.
(3.) Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012 Jan;481(7381):278–86.
(4.) Hong S, Hwang I, Lee YS, Park S, Lee WK, Fernandes T, et al. Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death. Cancer Lett. 2013 May; 331(2): 183-191.
(5.) Ting JP-Y, Kastner DL, Hoffman HM. CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol. 2006 Mar;6(3):183–95.
(6.) Vajjhala PR, Mirams RE, Hill JM. Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. J Biol Chem. 2012 Dec;287(50):41732–43.
(7.) Halff EF, Diebolder CA, Versteeg M, Schouten A, Brondijk THC, Huizinga EG. Formation and structure of a NAIP5-NLRC4 inflammasome induced by direct interactions with conserved N- and C-terminal regions of flagellin. J Biol Chem. 2012 Nov;287(46):38460–72.
(8.) Schroder K, Tschopp J. The inflammasomes. Cell. 2010 Mar;140(6):821–32.
(9.) Gross O, Thomas CJ, Guarda G, Tschopp J. The inflammasome: an integrated view. Immunol Rev. 2011 Sep;243(1):136–51.
(10.) Hsu L-C, Ali SR, McGillivray S, Tseng P-H, Mariathasan S, Humke EW, et al. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A. 2008 Jun;105(22):7803–8.
(11.) Wickliffe KE, Leppla SH, Moayeri M. Anthrax lethal toxin-induced inflammasome formation and cas-pase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol. 2008 Feb;10(2):332–43.
(12.) Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013 Jun;13(6):397–411.
(13.) Silverman WR, de Rivero Vaccari JP, Locovei S, Qiu F, Carlsson SK, Scemes E, et al. The pannexin 1 channel activates the inflammasome in neurons and astro-cytes. J Biol Chem. 2009 Jul ;284(27):18143–51.
(14.) Mankan AK, Kubarenko A, Hornung V. Immunology in clinic review series; focus on autoinflammatory diseases: inflammasomes: mechanisms of activation. Clin Exp Immunol. 2012 Mar;167(3):369–81.
(15.) Turner CM, Arulkumaran N, Singer M, Unwin RJ, Tam FWK. Is the inflammasome a potential therapeutic target in renal disease? BMC Nephrol. 2014 Jan;15:21.
(16.) Zhao Y, Yang J, Shi J, Gong Y-N, Lu Q, Xu H, et al. The NLRC4 inflammasome receptors for bacterial fla-gellin and type III secretion apparatus. Nature. 2011 Sep;477(7366):596–600.
(17.) Lightfield KL, Persson J, Trinidad NJ, Brubaker SW, Kofoed EM, Sauer J-D, et al. Differential requirements for NAIP5 in activation of the NLRC4 inflammasome. Infect Immun. 2011 Apr;79(4):1606–14.
(18.) Saiga H, Kitada S, Shimada Y, Kamiyama N, Okuya-ma M, Makino M, et al. Critical role of AIM2 in Myco-bacterium tuberculosis infection. Int Immunol. 2012 Oct;24(10):637–44.
(19.) Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cyto-solic dsDNA and forms a caspase-1-activating inflam-masome with ASC. Nature. 2009 Mar;458(7237):514–8.
(20.) Bandyopadhyay S, Lane T, Venugopal R, Parthasa-rathy PT, Cho Y, Galam L, et al. MicroRNA-133a-1 regulates inflammasome activation through uncou-pling protein-2. Biochem Biophys Res Commun. 2013 Sep;439(3):407–12.
(21.) Kahlenberg JM, Dubyak GR. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol. 2004 May;286(5):C1100–8.
(22.) Khakh BS, North RA. P2X receptors as cell-surface ATP sensors in health and disease. Nature. 2006 Aug;442(7102):527–32.
(23.) Shio MT, Tiemi Shio M, Eisenbarth SC, Savaria M, Vi-net AF, Bellemare M-J, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 2009 Aug;5(8):e1000559.
(24.) Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008 Aug;9(8):857–65.
(25.) Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagoso-mal destabilization. Nat Immunol. 2008 Aug;9(8):847–56.
(26.) So A, Busso N. The concept of the inflammasome and its rheumatologic implications. Joint Bone Spi-ne. 2014;81(5):381–464.
(27.) Mishra BB, Rathinam VAK, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, et al. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat Immunol. 2013 Jan;14(1):52–60.
(28.) Guarda G, Braun M, Staehli F, Tardivel A, Matt-mann C, Förster I, et al. Type I interferon inhibits
interleukin-1 production and inflammasome activa-tion. Immunity. 2011 Feb;34(2):213–23.
(29.) Oh JY, Ko JH, Lee HJ, Yu JM, Choi H, Kim MK, et al. Mesenchymal stem/stromal cells inhibit the NLRP3 inflammasome by decreasing mitochondrial reactive oxygen species. Stem Cells. 2014 Jun;32(6):1553–63.
(30.) Hu Y, Mao K, Zeng Y, Chen S, Tao Z, Yang C, et al. Tripartite-motif protein 30 negatively regulates NLRP3 inflammasome activation by modulating re-active oxygen species production. J Immunol. 2010 Dec;185(12):7699–705.
(31.) Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fer-nandes-Alnemri T, Alnemri ES, et al. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol. 2014 Apr;192(8):3881–8.
(32.) Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, et al. Phosphorylation of the adap-tor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammaso-me activity. Nat Immunol. 2013 Dec;14(12):1247–55.
(33.) Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deu-biquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012 Oct;287(43):36617–22.
(34.) Py BF, Kim M-S, Vakifahmetoglu-Norberg H, Yuan J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell. 2013 Jan;49(2):331–8.
(35.) Yuk J-M, Jo E-K. Crosstalk between autophagy and inflammasomes. Mol Cells. 2013 Nov;36(5):393–9.
(36.) Shi C-S, Shenderov K, Huang N-N, Kabat J, Abu-Asab M, Fitzgerald KA, et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012 Mar;13(3):255–63.
(37.) Dupont N, Jiang S, Pilli M, Ornatowski W, Bhatta-charya D, Deretic V. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. EMBO J. 2011 Nov;30(23):4701–11.
(38.) Aróstegui JI. [Pathophysiological mechanisms un-derlying cryopyrin-associated periodic syndromes: genetic and molecular basis and the inflammasome]. Med Clin (Barc). 2011 Jan;136 Suppl:22–8.
(39.) Anderson JP, Mueller JL, Misaghi A, Anderson S, Sivagnanam M, Kolodner RD, et al. Initial description of the human NLRP3 promoter. Genes Immun. 2008 Dec;9(8):721–6.
(40.) Conforti-Andreoni C, Ricciardi-Castagnoli P, Morte-llaro A. The inflammasomes in health and disease: from genetics to molecular mechanisms of autoin-flammation and beyond. Cell Mol Immunol. 2011 Mar;8(2):135–45.
(41.) Glinsky G V. SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways. Cell Cycle. 2008 Nov;7(22):3564–76.
(42.) Bryan NB, Dorfleutner A, Kramer SJ, Yun C, Rojanasa-kul Y, Stehlik C. Differential splicing of the apoptosis-associated speck like protein containing a caspase re-cruitment domain (ASC) regulates inflammasomes. J Inflamm (Lond). 2010 Jan;7:23-35.
(43.) Feng Q, Li P, Leung PCK, Auersperg N. Caspase-1zeta, a new splice variant of the caspase-1 gene. Geno-mics. 2004 Sep;84(3):587–91.
(44.) Bauernfeind F, Rieger A, Schildberg FA, Knolle PA, Schmid-Burgk JL, Hornung V. NLRP3 inflammasome activity is negatively controlled by miR-223. J Immu-nol. 2012 Oct;189(8):4175–81.
(45.) Bartel DP. MicroRNAs: target recognition and regula-tory functions. Cell. 2009 Jan;136(2):215–33.
(46.) Ghorai A, Ghosh U. miRNA gene counts in chro-mosomes vary widely in a species and biogenesis of miRNA largely depends on transcription or post-transcriptional processing of coding genes. Front Ge-net. 2014 Jan;5:100.
(47.) Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rai-ney A-A, Pich D, McInnes IB, et al. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 in-flammasome and IL-1β production. J Immunol. 2012 Oct;189(8):3795–9.
(48.) Halappanavar S, Nikota J, Wu D, Williams A, Yauk CL, Stampfli M. IL-1 receptor regulates microRNA-135b expression in a negative feedback mechanism during cigarette smoke-induced inflammation. J Immunol. 2013 Apr;190(7):3679–86.
(49.) Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, Santos MA, et al. MicroRNA-155 modula-tes the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A. 2009 Feb;106(8):2735–40.
(50.) Hardy TM, Tollefsbol TO. Epigenetic diet: impact on the epigenome and cancer. Epigenomics. 2011 Aug;3(4):503–18.
(51.) Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K. Epigenetic regulation of ASC/TMS1 expression: po-tential role in apoptosis and inflammasome function. Cell Mol Life Sci. 2014 May;71(10):1855–64.
(52.) Chowdhury S, Erickson SW, MacLeod SL, Cleves MA, Hu P, Karim MA, et al. Maternal genome-wide DNA methylation patterns and congenital heart defects. PLoS One. 2011 Jan;6(1):e16506.
(53.) Strickland FM, Richardson BC. Epigenetics in human autoimmunity. Epigenetics in autoimmunity - DNA methylation in systemic lupus erythematosus and beyond. Autoimmunity. 2008 May;41(4):278–86.
(54.) Raciti GA, Nigro C, Longo M, Parrillo L, Miele C, For-misano P, et al. Personalized medicine and type 2 diabetes: lesson from epigenetics. Epigenomics. 2014 Apr;6(2):229–38.
(55.) Lucas ME, Crider KS, Powell DR, Kapoor-Vazirani P, Vertino PM. Methylation-sensitive regulation of TMS1/ASC by the Ets factor, GA-binding protein-alpha. J Biol Chem. 2009 May;284(22):14698–709.
(56.) Stimson KM, Vertino PM. Methylation-mediated si-lencing of TMS1/ASC is accompanied by histone hypoacetylation and CpG island-localized changes in chromatin architecture. J Biol Chem. 2002 Feb;277(7):4951–8.
(57.) Ueki T, Takeuchi T, Nishimatsu H, Kajiwara T, Moriya-ma N, Narita Y, et al. Silencing of the caspase-1 gene occurs in murine and human renal cancer cells and causes solid tumor growth in vivo. Int J Cancer. 2001 Mar;91(5):673–9.
(58.) Wessels I, Fleischer D, Rink L, Uciechowski P. Chan-ges in chromatin structure and methylation of the human interleukin-1beta gene during monopoiesis. Immunology. 2010 Jul;130(3):410–7.
Descargas
Publicado
Cómo citar
Número
Sección
Licencia
Derechos de autor 2015 Iatreia
Esta obra está bajo una licencia internacional Creative Commons Atribución-CompartirIgual 4.0.
Los artículos publicados en la revista están disponibles para ser utilizados bajo la licencia Creative Commons, específicamente son de Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional.
Los trabajos enviados deben ser inéditos y suministrados exclusivamente a la Revista; se exige al autor que envía sus contribuciones presentar los formatos: presentación de artículo y responsabilidad de autoría completamente diligenciados.
