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NLRP3 During Macrophage Swelling Not Activate Caspase-1 in The Apoptosis-Associated Speck-like Protein Containing a CARD Forms Specks but Does Not Activate Caspase-1 in the Absence of NLRP3 during Macrophage Swelling This information is current as of September 27, 2021. Vincent Compan, Fátima Martín-Sánchez, Alberto Baroja-Mazo, Gloria López-Castejón, Ana I. Gomez, Alexei Verkhratsky, David Brough and Pablo Pelegrín J Immunol published online 31 December 2014 http://www.jimmunol.org/content/early/2014/12/31/jimmun Downloaded from ol.1301676 Supplementary http://www.jimmunol.org/content/suppl/2014/12/31/jimmunol.130167 http://www.jimmunol.org/ Material 6.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 31, 2014, doi:10.4049/jimmunol.1301676 The Journal of Immunology Apoptosis-Associated Speck-like Protein Containing a CARD Forms Specks but Does Not Activate Caspase-1 in the Absence of NLRP3 during Macrophage Swelling Vincent Compan,*,1 Fa´tima Martı´n-Sa´nchez,† Alberto Baroja-Mazo,† Gloria Lo´pez-Castejo´n,* Ana I. Gomez,† Alexei Verkhratsky,* David Brough,* and Pablo Pelegrı´n*,† Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is a key adaptor molecule re- quired for the inflammatory processes. ASC acts by bridging NLRP proteins, such as NLRP3, with procaspase-1 within the inflam- masome complex, which subsequently results in the activation of caspase-1 and the secretion of 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, such as a hypotonic environment, largely has been Downloaded from unexplored. In this article, we report that, under hypotonic conditions and independently of NLRP3, ASC was able to form specks 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 can present different oligomer- ization assemblies and represents an essential step in the activation of functional NLRP3 inflammasomes. The Journal of Immunology, 2015, 194: 000–000. http://www.jimmunol.org/ nflammation is a response against infection that is initiated of ASC monomers into a cytosolic speck called the pyroptosome by the activation of pattern recognition receptors (PRRs) on (2, 3). The pyroptosome is responsible for a specific type of cell I macrophages. PRRs are triggered by both pathogen- asso- death called pyroptosis, a mechanism mediated by caspase-1 ac- ciated molecular patterns (PAMPs) and danger-associated mo- tivation through which macrophages infected with intracellular lecular patterns (DAMPs), resulting in the production of pro- pathogens die rapidly, facilitating pathogen clearance (4). inflammatory cytokines (1). Signaling through PRRs of the TLR According to the current model for inflammasome activation, family induces synthesis of the inactive forms of IL-1b and IL-18, conformational changes in cytosolic PRRs of the nucleotide- two key proinflammatory cytokines that depend upon the activity binding and leucine-rich repeat receptor (NLR) family lead to by guest on September 27, 2021 of caspase-1 for their maturation and secretion. an interaction with caspase-1 (2). ASC is suggested to be necessary The adaptor molecule apoptosis-associated speck-like protein in bridging NLRP3 or AIM2 with procaspase-1 to form an containing a C-terminal caspase recruitment domain (CARD) inflammasome. In this situation, ASC has been found to self- (ASC or Pycard) is essential for caspase-1 activation in response to assemble into fiber-like structures from oligomers of NLRP3 or diverse disease- and pathogen-associated signals (2). ASC is a AIM2, culminating with the production of large protein aggre- cytosolic protein that contains a CARD and an N-terminal pyrin gates that amplify the activation of caspase-1 (5, 6). Other NLRs, domain (PYD). ASC can control the activation of caspase-1 by such as NLRC4 and NLRP1, can interact directly with caspase-1 two mechanisms: as a molecular adaptor between PYD and through their CARDs. However, recent studies revealed that CARD-containing signaling molecules within the inflammasome, ASC is also necessary for caspase-1 activation within NLRC4 and a cytosolic PRR multiprotein complex, or via the oligomerization NLRP1 complexes (7–10). In these situations, ASC assembles into *Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United contributed to the writing of the manuscript. P.P. conceived, designed, and supervised Kingdom; and †Unidad de Inflamacio´n y Cirugı´a Experimental, Centro de Investiga- this study, analyzed and interpreted experiments, and wrote the final manuscript. cio´n Biome´dica en Red en el A´ rea Tema´tica de Enfermedades Hepa´ticas y Digesti- Address correspondence and reprint requests to Dr. Pablo Pelegrı´nandDr.Fa´tima vas, Hospital Clı´nico Universitario Virgen de la Arrixaca, Instituto Murciano de Martı´n-Sa´nchez, Unidad de Inflamacio´nyCirugı´a Experimental, Hospital Clı´nico Uni- Investigacio´n Biosanitaria-Arrixaca, 30120 Murcia, Spain versitario Virgen de la Arrixaca, Carretera Madrid Cartagena s/n, 30120 Murcia, Spain. 1Current address: Institut de Ge´nomique Fonctionnelle, Centre National de la E-mail addresses: pablo.pelegrin@ffis.es (P.P.) and fatima.martin@ffis.es (F.M.-S.) Recherche Scientifique-Unite´ Mixte de Recherche 5203, INSERM U661, Universite´ The online version of this article contains supplemental material. de Montpellier 1 & 2, Montpellier, France. Abbreviations used in this article: ASC, apoptosis-associated speck-like protein con- ORCID: 0000-0002-9688-1804 (P.P.). taining a C-terminal caspase recruitment domain; BAPTA-AM, 1,2-bis(2-aminophe- Received for publication July 15, 2013. Accepted for publication November 24, noxy)ethane-N,N,N9,N9-tetraacetic acid tetrakis-acetoxymethyl ester; BMDM, bone 2014. marrow–derived macrophage; BRET, bioluminescence resonance energy transfer; CARD, caspase recruitment domain; coIP, coimmunoprecipitation; Ct, C terminus; This work was supported by grants from Plan Nacional de Investigacio´n Cientı´fica, DAMP, danger-associated molecular pattern; LDH, lactate dehydrogenase; Luc, Desarrollo e Innovacio´n Tecnolo´gica 1 2008–2011–Instituto Salud Carlos III–Fondo Renilla luciferase; mOsm, milliosmole; MSU, monosodium urate; NLR, nucleotide- Europeo de Desarrollo Regional (EMER07/049 and PI09/0120), Fundacio´nSe´neca binding and leucine-rich repeat receptor; PAMP, pathogen-associated molecular pat- (11922/PI/09), and European Research Council (ERC-2013-CoG 614578). V.C. was tern; PRR, pattern recognition receptor; PYD, pyrin domain; RVD, regulatory volume supported by a grant from The Wellcome Trust. decrease; shRNA, short hairpin RNA; TAK1, TGF-b–activated kinase 1; TRP, tran- V.C. contributed to the design, execution, and analysis of experiments in Figs. 1A, sient receptor potential; TRPV2, TRP vanilloid 2. 1D, 2–4, 7B–G, 7I, 8A, 8C, and 8D. F.M.-S., A.B.-M., G.L.-C., and A.I.G. per- formed, analyzed, and interpreted the in vitro experiments in Figs. 1B, 1C, 1E, 5, Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 6, 7H, 7J, 7K, and 8B. D.B. provided NLRP3-deficient mice. V.C., D.B., and A.V. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301676 2 ASC SPECK FORMATION DURING CELL SWELLING a ring-like structure surrounding NLRC4 oligomers (11). These data fluorescent-conjugated secondary Abs were from Jackson Immuno- suggest that ASC is essential for inflammasome activity in general Research. and that it could present different oligomerization assemblies. All animal experiments were carried out under the Animals (Scientific Procedures) Act 1986. Peritoneal and bone marrow macrophages were The NLRP3 inflammasome is activated by diverse DAMPs and obtained from male C57BL/6J mice or from Nlrp32/2 or double Casp-1- PAMPs. Its activation by DAMPs is central for sterile inflammatory Casp112/2 mice, as previously described (14, 24, 25). THP-1 and HEK293 responses and for amplification of infection-induced inflammation cells were maintained in RPMI 1640 and DMEM:F12 (1:1) media, re- (2). Endogenous DAMPs activating NLRP3 can be classified into spectively, supplemented with 10% FCS, 2 mM GlutaMAX, and 1% pen/ strep (Invitrogen). Lipofectamine 2000 reagent (Invitrogen) was used two main categories: (1) soluble activators, such as extracellular ATP for transfecting HEK293 cells per the manufacturer’s instructions.
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