Pelegrín Vivancos, Pablo

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Pelegrín Vivancos, Pablo

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Pelegrín Vivancos, Pablo

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Universidad de Murcia. Departamento de Bioquímica y Biología Molecular"B" e Inmunología

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Cell volume regulation modulates NLRP3 inflammasome activation
(Elsevier, 2012-09-21) Compan, Vincent; Baroja Mazo, Alberto; López Castejón ∙, Gloria; Gómez, Ana I.; Angosto, Diego; Montero, María T.; Herranz, Antonio S.; Bazán, Eulalia; Reimers, Diana; Martínez Cáceres, Carlos Manuel; Mulero Méndez, Victoriano Francisco; Pelegrín Vivancos, Pablo; Anatomía y Anatomía Patológica Comparadas
Cell volume regulation is a primitive response to alterations in environmental osmolarity. The NLRP3 inflammasome is a multiprotein complex that senses pathogen- and danger-associated signals. Here, we report that, from fish to mammals, the basic mechanisms of cell swelling and regulatory volume decrease (RVD) are sensed via the NLRP3 inflammasome. We found that a decrease in extracellular osmolarity induced a K+-dependent conformational change of the preassembled NLRP3-inactive inflammasome during cell swelling, followed by activation of the NLRP3 inflammasome and caspase-1, which was controlled by transient receptor potential channels during RVD. Both mechanisms were necessary for interleukin-1β processing. Increased extracellular osmolarity prevented caspase-1 activation by different known NLRP3 activators. Collectively, our data identify cell volume regulation as a basic conserved homeostatic mechanism associated with the formation of the NLRP3 inflammasome and reveal a mechanism for NLRP3 inflammasome activation.
Open Access
Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation
(American Association for the Advancement of Science, 2021-09-15) Angosto-Bazarra, Diego; Alarcón-Vila, Cristina; Baños, Maria C; Hafner-Bratkovič, Iva; Oliva, Baldomero; Pelegrín Vivancos, Pablo; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
The NLRP3 inflammasome is activated in response to a wide range of stimuli and drives diverse inflammatory diseases. The decrease of intracellular K+ concentration is a minimal upstream signal to most of the different NLRP3 activation models. Here we found that cellular K+ efflux induces a stable structural change in the inactive NLRP3 promoting an open conformation as a step preceding activation. This conformational change is facilitated by the presence of the specific NLRP3 FISNA domain and a unique flexible linker sequence between the PYD and FISNA domains. This linker is also important to facilitate the ensemble of NLRP3PYD into a seed structure for ASC oligomerization. The introduction of the NLRP3 PYD-linker-FISNA sequence into NLRP6 resulted in a chimeric receptor able to be activated by K+ efflux-specific NLRP3 activators and promoted an in vivo inflammatory response to uric acid crystals. Our results establish that the N-terminal sequence between PYD and NACHT domain of NLRP3 is key for inflammasome activation.
Open Access
CD14 release induced by P2X7 receptor restrict inflammation and increases survival during sepsis
(eLife Sciences Publications, 2020-11-26) Alarcón-Vila, Cristina; Baroja-Mazo, Alberto; Torre-Minguela, Carlos de; Martínez-García, Juan J.; Martínez-Banaclocha, Helios; Gracia-Palenciano, Carlos; Martínez Cáceres, Carlos Manuel; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
P2X7 receptor activation induces the release of different cellular proteins, such as CD14, a glycosylphosphatidylinositol (GPI)-anchored protein to the plasma membrane important for LPS signaling via TLR4. Circulating CD14 has been found at elevated levels in sepsis, but the exact mechanism of CD14 release in sepsis has not been established. Here we show for first time that P2X7 receptor induces the release of CD14 in extracellular vesicles, resulting in a net reduction in macrophage plasma membrane CD14 that functionally affects LPS, but not monophosphoryl lipid A, pro-inflammatory cytokine production. Also, we found that during a murine model of sepsis, P2X7 receptor activity is important for maintaining elevated levels of CD14 in biological fluids and a decrease in its activity results in higher bacterial load and exacerbated organ damage, ultimately leading to premature deaths. Our data reveal that P2X7 is a key receptor for helping to clear sepsis because it maintains elevated concentrations of circulating CD14 during infection.
Open Access
The total electric charge and time of application of galvanic currents to macrophages can optimize the release of IL-1β with low cell death
(Nature Research, 2024-12-28) Peñín Franc, Alejandro; García Vidal, José Antonio; Gómez, Ana Isabel; Escolar Reina, Pilar; Medina Mirapeix, Francesc; Pelegrín Vivancos, Pablo; Fisioterapia
Galvanic current has been emerging as a novel therapy to regenerate chronic tissue lesions, including musculoskeletal and dermatological lesions. Recently, the NLRP3 inflammasome and IL-1β release have been identified as a signaling pathway triggered upon galvanic current application. However, the parameters for the clinical application of galvanic current remain subjective to the experience of the facultative in charge. In this study we used an in vitro model of macrophage culture and application of different combinations of the parameters of galvanic current to study IL-1β production and cell death. Increasing electric charge of galvanic current induces the release of IL-1β, but electric charges equal or higher to 144 mC also increase cell death. The release of IL-1β have a substantial variation within different electric charge of galvanic currents, being increased by decreasing the current and increasing the time of current application. Within the range of current intensities studied, the most optimal protocol for maximizing IL-1β release without inducing cell death was identified at electric charges equal to or near 144 mC, applied over a total duration of approximately 25 s. Our findings lay the groundwork for future in vivo studies assessing different electric charge of galvanic current, with the aim of yielding clinically relevant outcomes.
Open Access
Phylogeny of cytokines: molecular cloning and expression analysis of sea bass Dicentrarchus labrax interleukin-1b
(2001) Scapigliati, G.; Buonocore, F.; Bird, S.; Zou, J.; Falasca, C.; Prugnoli, D.; Secombes, C. J.; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
In this paper the cloning of interleukin-1b (IL-1b) from the fish Dicentrarchus labrax (sea bass) is described. Using degenerate primers designed from known IL-1b sequences, a cDNA fragment was amplified by PCR and elongated by 3’ and 5’ RACE to give the full-length coding sequence for sea bass IL-1. The cDNA is 1292 bp, lacks a putative ICE cut site, and codes for a deduced peptide of 29.4 kDa with a pI of 5.1. Sequence analysis showed highest amino acid similarity with rainbow trout (62%), Xenopus (46%), and carp (45.5%) IL-1b sequences. Expression studies show that sea bass IL-1b can be upregulated by bacterial lipopolysaccharide both in vitro and in vivo in leucocytes from blood, head-kidney, spleen, gills and liver, whereas the IL-1b transcript was not detectable in thymus and gut-associated lymphoid tissue. Northern blot analysis with head-kidney leucocyte RNA showed a main LPS- upregulated band at 1.3 kb, and two minor bands at 0.9 and 3.0 kb, respectively. Phylogenetic comparisons with IL-1b from other vertebrates is presented.
Open Access
Danger signals released during cold ischemia storage activate NLRP3 inflammasome in myeloid cells and influence early allograft function in liver transplantation
(Elsevier, 2022-12-19) Lucas-Ruiz, Fernando; Mateo, Sandra V.; Jover-Aguilar, Marta; Alconchel, Felipe; Martínez-Alarcón, Laura; Torre-Minguela, Carlos de; Vidal-Correoso, Daniel; Villalva-López, Francisco; López-López, Víctor; Rios-Zambudio, Antonio; Pons Miñano, José Antonio; Ramírez, Pablo; Baroja-Mazo, Alberto; Pelegrín Vivancos, Pablo; Medicina
Background Innate immunity plays a fundamental role in solid organ transplantation. Myeloid cells can sense danger signals or DAMPs released after tissue or cell damage, such as during ischemia processes. This study aimed to identify DAMPs released during cold ischemia storage of human liver and analyze their ability to activate the inflammasome in myeloid cells and the possible implications in terms of short-term outcomes of liver transplantation. Methods 79 samples of organ preservation solution (OPS) from 79 deceased donors were collected after cold static storage. We used different analytical methods to measure DAMPs in these end-ischemic OPS (eiOPS) samples. We also used eiOPS in the human macrophage THP-1 cell line and primary monocyte cultures to study inflammasome activation. Findings Different DAMPs were identified in eiOPS, several of which induced both priming and activation of the NLRP3 inflammasome in human myeloid cells. Cold ischemia time and donation after circulatory death negatively influenced the DAMP signature. Moreover, the presence of oligomeric inflammasomes and interleukin-18 in eiOPS correlated with early allograft dysfunction in liver transplant patients. Interpretation DAMPs released during cold ischemia storage prime and activate the NLRP3 inflammasome in liver macrophages after transplantation, inducing a pro-inflammatory environment that will complicate the outcome of the graft. The use of pharmacological blockers targeting DAMPs or the NLRP3 inflammasome in liver ischemia during static cold storage or through extracorporeal organ support could be a suitable strategy to increase the success of liver transplantation.
Open Access
The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
(Nature, 2014) Baroja-Mazo, Alberto; Gomez, Ana I.; Amores-Iniesta, Joaquín; Compan, Vincent; Barberá-Cremades, María; Yagüe, Jordi; Ruiz-Ortiz, Estibaliz; Antón, Jordi; Buján, Segundo; Couillin, Isabelle; Brough, David; Arostegui, Juan I.; Martínez Cáceres, Carlos Manuel; Martín Sánchez, María Rosario Fátima; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
NLRP3 inflammasome assembly activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β, and thereby plays a central role in the inflammatory response and in diverse human diseases. Here we report that upon caspase-1 activation oligomerized NLRP3-inflammasome particles are released from macrophages. Recombinant oligomeric protein particles composed of the adapter protein ASC or the cryopyrin-associated periodic syndromes (CAPS) mutant NLRP3 p.D303N, stimulate further caspase-1 activation extracellularly, and also intracellularly upon phagocytosis by surrounding macrophages. ASC oligomeric particles were found in the serum of patients with active CAPS, but not in patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3-inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
Open Access
Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins
(Nature Research, 2016-07-01) Martín Sánchez, María Rosario Fátima; Tyrkalska, Sylwia D.; Candel Camacho, Sergio; Angosto, Diego; Gómez Abellán, Victoria; García Moreno, Diana; Zapata Pérez, Rubén; Sánchez Ferrer, Álvaro; Pelegrín Vivancos, Pablo; Mulero Méndez, Victoriano Francisco; Sepulcre Cortés, María Pilar; Farmacología
Inflammasomes are cytosolic molecular platforms that alert the immune system about thepresence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4),an IFNg-inducible GTPase protein harbouring a C-terminal CARD domain, is required for theinflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo.Despite the presence of the CARD domain, Gbp4 requires the universal inflammasomeadaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophilsare recruited to the infection site through the inflammasome-independent production of thechemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearancethrough the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our resultspoint to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis andbacterial clearance by neutrophils and suggest that transient activation of the inflammasomemay be used to treat bacterial infections.
Open Access
Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
(Nature Research, 2024-02-06) Molina-López, Cristina; Hurtado-Navarro, Laura; Garcia, Carlos J.; Angosto-Bazarra, Diego; Vallejo, Fernando; Marques-Soares, Joana R.; Vargas, Carmen; Bujan-Rivas, Segundo; Tomás-Barberán, Francisco A.; Arostegui, Juan I.; Pelegrín Vivancos, Pablo; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1b production. Although these are gain-of-function variants characterised by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4A. The constitutively active NLRP3-inflammasome is responsive to the selective NLRP3 inflammasome inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-kB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1b production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1b–dependent inflammatory episodes through immunometabolism modulation.
Open Access
Early endosome autoantigen 1 regulates IL-1β release upon caspase-1 activation independently of gasdermin D membrane permeabilization
(Nature Research, 2019-04-08) Martín Sánchez, María Rosario Fátima; Baroja Mazo, Alberto; Compan, Vince; Tapia Abellán, Ana; Coullin, Isabelle; Pelegrín Vivancos, Pablo; Farmacología
Unconventional protein secretion represents an important process of the inflammatory response.The release of the pro-inflammatory cytokine interleukin (IL)-1β which burst during pyroptosis asa consequence of gasdermin D plasma membrane pore formation, can also occur through otherunconventional secretion pathways dependent on caspase-1 activation. However, how caspase-1mediates cytokine release independently of gasdermin D remains poorly understood. Here weshow that following caspase-1 activation by different inflammasomes, caspase-1 cleaves earlyendosome autoantigen 1 (EEA1) protein at Asp127/132 . Caspase-1 activation also results in the releaseof the endosomal EEA1 protein in a gasdermin D-independent manner. EEA1 knock-down resultsin adecreased release of caspase-1 and IL-1β, but the pyroptotic release of other inflammasomecomponents and lactate dehydrogenase was not affected. This study shows how caspase-1 control therelease of EEA1 and IL-1β in a pyroptotic-independent manner