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Manner Via Caspase-8 in an RIP3 Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1 β and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner This information is current as of October 2, 2021. Lukas Bossaller, Ping-I Chiang, Christian Schmidt-Lauber, Sandhya Ganesan, William J. Kaiser, Vijay A. K. Rathinam, Edward S. Mocarski, Deepa Subramanian, Douglas R. Green, Neal Silverman, Katherine A. Fitzgerald, Ann Marshak-Rothstein and Eicke Latz Downloaded from J Immunol 2012; 189:5508-5512; Prepublished online 9 November 2012; doi: 10.4049/jimmunol.1202121 http://www.jimmunol.org/content/189/12/5508 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/11/12/jimmunol.120212 Material 1.DC1 References This article cites 30 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/189/12/5508.full#ref-list-1 by guest on October 2, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1b and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner Lukas Bossaller,* Ping-I Chiang,* Christian Schmidt-Lauber,† Sandhya Ganesan,* ‡ ‡ William J. Kaiser, Vijayx A. K. Rathinam,*{ Edward S. Mocarski, Deepa Subramanian, Douglas R. Green, Neal Silverman,*x ‖ Katherine A. Fitzgerald,* Ann Marshak-Rothstein,†, ,1 and Eicke Latz*, ,#,1 Fas, a TNF family receptor, is activated by the mem- syndrome carry inherited mutations in Fas (4). Similar to other brane protein Fas ligand expressed on various immune death-inducing signaling receptors, Fas signaling also has cells. Fas signaling triggers apoptosis and induces in- nonapoptotic functions in cellular proliferation and differen- Downloaded from flammatory cytokine production. Among the Fas- tiation and cytokine activation (1). However, little is known induced cytokines, the IL-1b family cytokines require about the consequences of Fas signaling on cytokine activation proteolysis to gain biological activity. Inflammasomes, for the control of tumorous, damaged, or infected cells or for which respond to pathogens and danger signals, cleave the development of pathologies in autoimmune diseases. In cells IL-1b cytokines via caspase-1. However, the mecha- of the adaptive-immune system, Fas signaling is important for the regulation of apoptosis and, therefore, is essential for the nisms by which Fas regulates IL-1b activation remain http://www.jimmunol.org/ unresolved. In this article, we demonstrate that macro- establishment of self-tolerance (5, 6). phages exposed to TLR ligands upregulate Fas, which Of importance for inflammatory conditions, Fas signaling in cells of the innate immune system, such as neutrophils, renders them responsive to receptor engagement by Fas dendritic cells, or macrophages, can mediate the production ligand. Fas signaling activates caspase-8 in macro- and activation of proinflammatory cytokines of the IL-1b phages and dendritic cells, leading to the maturation b family, as well as chemokines (7–9). The proinflammatory of IL-1 and IL-18 independently of inflammasomes effect of Fas signaling on innate immune cells is particularly or RIP3. Hence, Fas controls a novel noncanonical IL- noticeable in microbially infected cells or in cells that have b by guest on October 2, 2021 1 activation pathway in myeloid cells, which could been primed by stimulants, such as TLR ligands (10). play an essential role in inflammatory processes, tumor The proinflammatory IL-1b family of cytokines is controlled surveillance, and control of infectious diseases. The at the transcriptional and posttranscriptional levels and pro- Journal of Immunology, 2012, 189: 5508–5512. duced as biologically inactive precursors, which, upon proteo- lytic processing, become active cytokines. Several proteases have as (also called CD95, APO-1, or TNFRSF6) is a been implicated in the processing of IL-1b cytokines (11); membrane protein that belongs to the TNFR family. among these, the best studied is caspase-1. Caspase-1 activity is F Binding of its physiological ligand, Fas ligand (FasL), to controlled by inflammasomes, which are multiprotein signaling Fas causes apoptosis, a process that is thought to be critical for complexes that detect microbial-derived molecular signatures the control of tumor cells, infected cells, or otherwise damaged or endogenous danger signals (12). However, Fas-mediated IL- cells (1). Fas-mediated killing of immune cells is important for 1b activation is caspase-1 independent; thus, it remains to be immune homeostasis, because mice with spontaneous muta- determined how Fas induces IL-1b activation (7, 8). tions in Fas or FasL develop autoimmunity (2, 3), and a frac- Several lines of evidence suggest the existence of a noncanonical tion of human patients with autoimmune lymphoproliferative IL-1b activation pathway that involves caspase-8 and receptor- *Department of Infectious Diseases and Immunology, University of Massachusetts Address correspondence and reprint requests to Dr. Eicke Latz, Institute of Innate Medical School, Worcester, MA 01605; †Division of Rheumatology, University of Immunity, Sigmund-Freud-Strasse 25, University of Bonn, 53127 Bonn, Germany. Massachusetts Medical School, Worcester, MA 01605; ‡Department of Immunology E-mail address: [email protected] and Microbiology, Emory Vaccine Center, Emory University School of Medicine, x The online version of this article contains supplemental material. Atlanta, GA 30322; Boston University School of Medicine, Boston, MA 02118; { Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN Abbreviations used in this article: BMDC, bone marrow–derived dendritic cell; BMDM, ‖ 38105; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany; and bone marrow–derived macrophage; CL, cell lysate; dAdT, poly(deoxyadenylic-thymi- #German Center for Neurodegenerative Diseases, 53127 Bonn, Germany dylic) acid; FasL, Fas ligand; IAP, inhibitor of apoptosis protein; KO, knockout; mFasL, Fas ligand–expressing microvesicle; Neo, control microvesicles from neomycin-resistance 1A.M.-R. and E.L. contributed equally to this work. vector-transfected cells; RIP, receptor-interacting protein; SN, supernatant. Received for publication August 1, 2012. Accepted for publication October 18, 2012. Ó This work was supported by National Institutes of Health Grants HL093262 (to E.L.), Copyright 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 CA90691 and AR050256 (to A.M.-R.), AI057159 (to V.A.K.R.), and AI083713 (to K.A.F. and E.L.); the Alliance for Lupus Research (to A.M.-R.); and German Research Foundation Grants SFB670, SFB645, SFB704, and KFO177 (to E.L.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1202121 The Journal of Immunology 5509 interacting protein (RIP) kinases. In primed macrophages, ac- inflammasome activators (18, 19). Inflammasomes can be ac- tivation of the TRIF-engaging TLR3 and TLR4 led to IL-1b tivated in response to necrosis-inducing agents (20) and, because maturation via caspase-8 in conditions in which protein syn- inflammasomes control IL-1b maturation, we hypothesized that thesis was pharmacologically inhibited (13). Furthermore, they may be engaged downstream of Fas. experimentsusingantagonistsofinhibitorsofapoptosisproteins BMDMs require a priming signal for the upregulation of (IAPs) revealed IL-1b maturation via the NLRP3 inflamma- NLRP3 and pro–IL-1b that allow inflammasome activation by some and caspase-1, as well as via a caspase-8–dependent danger signals (21). Although a 2-h priming step is sufficient pathway. Notably, the protein kinase RIP3, a key enzyme in to render BMDMs responsive to NLRP3 activators, we found the crossroads between apoptosis and necrosis, and reactive that IL-1b release in response to mFasL required significantly oxygen species were required for both of these pathways (14). longer priming periods (Fig. 1A, Supplemental Fig 1A). Finally, dectin-1 can activate IL-1b via caspase-8 in a pathway Control microvesicles (Neo) did not stimulate IL-1b release at that requires the inflammasome adapter molecule ASC (15). either time point after LPS priming. In contrast to resident In this article, we demonstrate that Fas-mediated IL-1b acti- peritoneal macrophages, BMDMs constitutively express only vation does not require the inflammasome components NLRP3, low amounts of Fas (9). Therefore, we assessed whether ASC, or caspase-1; instead, it proceeds in a process requiring the priming of cells could induce Fas expression on BMDMs. adapter molecule FADD and caspase-8. In contrast to previously Indeed, TLR4 or TLR7 priming for 24 h led to increased described caspase-8–activation pathways, Fas-induced IL-1b staining of membrane Fas. Notably, the IL-1b response (Fig. maturation via caspase-8 proceeds
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