Browsing by Subject "Inflamasoma"

Now showing 1 - 5 of 5
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    Apoptosis-associated speck-like protein containing CARD forms specks but does not activate caspase-1 in the absence of NLRP3 during macrophage swelling
    (The American Association of Immunologists, Inc., 2015) Compan, Vincent; Martín-Sánchez, Fátima; Baroja-Mazo, Alberto; López-Castejón, Gloria; Gomez, Ana I.; Verkhratsky, Alexei; Brough, David; Pelegrin Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
    Apoptosis-associated speck-like protein containing a CARD (ASC) is a key adaptor molecule required for inflammatory processes. ASC acts by bridging NLRP proteins, such as NLRP3, with pro-caspase-1 within the inflammasome complex that subsequently results in the activation of caspase-1 and the secretion of interleukin (IL)-1b and IL-18. In response to bacterial infection, ASC also forms specks by self-oligomerization to activate caspase-1 and induce pyroptosis. Hitherto the role of these specks in NLRP3 inflammasome activation in response to danger signals is largely unexplored. Here we report that under hypotonic conditions, ASC formed specks independently of NLRP3 that did not activate caspase-1. These specks were not associated with pyroptosis and were controlled by Transient Receptor Potential Vanilloid 2 channel mediated signaling. However, interaction with NLRP3 enhanced ASC speck formation leading to fully functional inflammasomes and caspase-1 activation. This study reveals that the ASC speck could present different oligomerization assemblies and represents an essential step in the activation of functional NLRP3 inflammasomes.
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    Cell volume regulation modulates NLRP3 inflammasome activation
    (Cell Press, 2012) Compan, Vincent; Baroja-Mazo, Alberto; Lopez-Castejón, Gloria; Gomez, Ana I.; Martínez, Carlos M.; Angosto, Diego; Montero, María T.; Herranz, Antonio S.; Bazán, Eulalia; Reimers, Diana; Mulero, Victoriano; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
    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 the basic mechanisms of cell swelling and regulatory volume decrease (RVD) are sensed from fish to mammals by the NLRP3 inflammasome. We found that a decrease in extracellular osmolarity induced (i) a K+-dependent conformational change of the preassembled NLRP3-inactive inflammasome during cell swelling, followed by (ii) activation of the NLRP3 inflammasome and caspase-1, which was controlled by Transient Receptor Potential (TRP) channels during RVD. Both mechanisms were necessary for interleukin-1b processing. Increased extracellular osmolarity prevented caspase-1 activation by different known NLRP3 activators. Collectively, our data place cell volume regulation as a basic conserved homeostatic mechanism associated with the formation of the NLRP3 inflammasome and provides a mechanism for NLRP3 inflammasome activation.
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    Pannexin-1 mediates large pore formation and interleukin-1ß release by the ATP-gated P2X7 receptor
    (2006) Pelegrin, Pablo; Surprenant, Annmarie; Bioquímica y Biología Molecular B e Inmunología
    P2X(7) receptors are ATP-gated cation channels; their activation in macrophage also leads to rapid opening of a membrane pore permeable to dyes such as ethidium, and to release of the pro-inflammatory cytokine, interleukin-1beta (IL-1beta). It has not been known what this dye-uptake path is, or whether it is involved in downstream signalling to IL-1beta release. Here, we identify pannexin-1, a recently described mammalian protein that functions as a hemichannel when ectopically expressed, as this dye-uptake pathway and show that signalling through pannexin-1 is required for processing of caspase-1 and release of mature IL-1beta induced by P2X(7) receptor activation.
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    The inflammasome adaptor protein ASC promotes amyloid deposition in cryopyrin-associated periodic syndromes
    (EMBO Press, 2025) Alarcón-Vila, Cristina; Hurtado-Navarro, Laura; Mateo, Sandra V; Peñín-Franch, Alejandro; Martínez, Carlos M; Molina-López, Cristina; Baños, Maria C; Gómez, Ana I; Gómez-Román, Jorge; Baroja-Mazo, Alberto; Arostegui, Juan I; Palmou-Fontana, Natalia; Martínez-García, Juan J; Pelegrin, P; Bioquímica y Biología Molecular B e Inmunología
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    The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
    (Nature, 2014) Baroja-Mazo, Alberto; Martín-Sánchez, Fátima; Gomez, Ana I.; Martínez, Carlos M.; Amores-Iniesta, Joaquín; Compan, Vincent; Barberá-Cremades, María; Yagüe, Jordi; Ruiz-Ortiz, Estibaliz; Antón, Jordi; Buján, Segundo; Couillin, Isabelle; Brough, David; Arostegui, Juan I.; Pelegrin 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.