Anales de la RANM

29 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 S U P L E M E N T O I SIMPOSIO · JÓVENES INVESTIGADORES Libro de Abstracts An RANM. 2021;138(03).supl01: 29 - 54 con inhibidores de NLRP3, presentan una mayor supervivencia en modelos de sepsis. No obstante, en clínica los pacientes con sepsis desarrollan un estado inmunosupresor tras la respuesta inflama- toria, y es debido a ese estado inmunosupresor y las complicaciones causadas por infecciones secundarias, las que comprometen la viabilidad de los pacientes. Por tanto, el manejo clínico de los pacientes con sepsis es complicado y a día de hoy no existe un marcador pronostico que discrimine de forma temprana aquellos pacientes que vayan a desarrollar complicaciones. La activación NLRP3 en muestras de sangre de pacientes sépticos a tiempos tempranos resulto en la estratificación de dichos pacientes, al haber un grupo con una deficiencia en su activación. Este grupo tuvo más complicaciones y acumuló la mayoría de muertes, sugiriendo que la determinación del grado de activación del inflamasoma NLRP3 podría consti- tuir un marcador temprano para poder pronosticar la evolución de los pacientes sépticos. Agradecimientos: Este trabajo ha sido financiado por proyectos de investigación de FEDER/ Ministerio de Ciencia, Innovación y Univer- sidades-Agencia Estatal de Investigación (SAF2017-88276-R; PID2020-116709RB-I00), Fundación Séneca (20859/PI/18, 21081/PDC/19 y 00003/COVI/20), Instituto de Salud Carlos III (DTS21/00080), Comisión Europea H2020-SC1- 2020-Single-Stage-RTD (965196 - PlasticHeal) y del European Research Council (ERC-2013-CoG 614578 y ERC-2019-PoC 899636). The inflammatory response is a main effector mechanism of the innate immune system and it is coordinated by a signalling network triggered by different receptors and soluble factors, among them the pattern recognition receptors and cytokines play a central role. Inflammation coordinate the elimina- tion of pathogens and initiate the regeneration of tissues and therefore is triggered by the engage- ment of these receptors in innate immune cells by ligand molecules from pathogens or necrotic cells. Dysregulation of the inflammatory response may lead to cornification and the development of chronic inflammatory, metabolic or degenerative diseases. The inflammasome is formed by an intracellular receptor of the pattern recognition family and among the different inflammasomes, the NLRP3 inflam- masome, is the main that recognise pathogen- and host-derived signals. Gain-of-function mutations in NLRP3 gene are associated to auto-inflammatory syndromes. The activation of the NLRP3 inflam- masome follows a series of oligomerization steps that culminate with the activation of caspase-1 (Figure 1). This caspase is able to process different pro-cytokines of the interleukin (IL)-1 family to their active forms, such as IL-1β and IL-18. Also, caspase-1 process the protein gasdermin D, and its amino-terminal fragment oligomerize and form pores in the plasma membrane that are a release pathway for IL-1β and IL-18. The pores formed by gasdermin D in the plasma membrane could be repaired, but if caspase-1 activation prolongs in the time, the cell swells by massive water intake and results in a type of inflammatory type of necrosis cell death called pyroptosis. Pyroptosis also results in the release of other intracellular content, as inflammasome oligomers and mitochondrial DNA that contributes to the propagation of the inflamma- tory response. Sepsis is a systemic inflammatory response syndrome induced by an infection and constitute the main cause of deaths in the critical care units of the hospitals. The NLRP3 inflammasome participate in the inflammatory response in sepsis, and knock-out mice for NLRP3 or mice treated with specific NLRP3 inhibitors present an increased survival in sepsis models. However, in clinics septic patients develop an immunosuppression state after the inflammatory response that is the causative of secondary infections and complications that compromise the survival of septic patients. Therefore, the clinical management of septic patients is complex and up to date, there is any available prognostic marker to early discrimi- nate septic patients that will develop future compli- cations. The activation of the NLRP3 inflamma- some in blood samples from septic patients at early time-points was able to stratify these patients, with a group presenting a defect in its activation. This septic patient group presented more complications and accumulated the majority of deaths, suggesting that the determination of the activation level of NLRP3 inflammasome could constitute a promising early prognostic marker to evaluate the evolution of the septic patients. Acknowledgements This work was supported by grants to P.P. from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (grant SAF2017-88276-R; PID2020- 116709RB-I00), Fundación Séneca (grants 20859/ PI/18, 21081/PDC/19 and 0003/COVI/20), Instituto de Salud Carlos III (DTS21/00080), European Commission H2020-SC1-2020-Single-Stage-RTD (965196 - PlasticHeal) and European Research Council (grants ERC-2013-CoG 614578 and ERC-2019-PoC 899636). ACTIVACIÓN Y REGULACIÓN DEL INFLAMASOMA NLRP3 CON MUTACIONES PRESENTES EN EL SÍNDROME PERIÓDICO ASOCIADO A CRIOPIRINA ACT I VAT I ON AND REGULAT I ON OF THE NLRP3 I NFLAMMASOME WI TH MUTAT I ONS L I NKED TO CRYOPYRIN ASSOCIATED PERIODIC SYNDROMES Cristina Molina-López 1 , Diego Angosto-Bazarra 1 , Ana Tapia-Abellán 1 , Laura Hurtado-Navarro 1 , Pablo Pelegrín 1,2 1 Instituto Murciano de Investigaciones Biosanitarias (IMIB- Arrixaca), Hospital Universitario Virgen de la Arrixaca, Murcia, España 2 Departamento de Bioquímica, Biología Molecular B e Inmunología, Facultad de Medicina, Universidad de Murcia, Murcia, España