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Cutting Edge: Blockade of Inhibitor of Apoptosis Proteins Sensitizes Cutting Edge: Blockade of Inhibitor of Apoptosis Proteins Sensitizes Neutrophils to TNF- but Not Lipopolysaccharide-Mediated Cell Death and IL-1 β Secretion This information is current as of September 25, 2021. Kaiwen W. Chen, Kate E. Lawlor, Jessica B. von Pein, Dave Boucher, Motti Gerlic, Ben A. Croker, Jelena S. Bezbradica, James E. Vince and Kate Schroder J Immunol 2018; 200:3341-3346; Prepublished online 16 April 2018; Downloaded from doi: 10.4049/jimmunol.1701620 http://www.jimmunol.org/content/200/10/3341 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/04/14/jimmunol.170162 Material 0.DCSupplemental References This article cites 26 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/200/10/3341.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 2021 • 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Cutting Edge Immunology Cutting Edge: Blockade of Inhibitor of Apoptosis Proteins Sensitizes Neutrophils to TNF- but Not Lipopolysaccharide-Mediated Cell Death and IL-1b Secretion †,‡,1 ,1 Kaiwen W. Chen,*x Kate E. Lawlor,{ Jessica B. von Pein,* Dave Boucher,* Motti Gerlic, Ben A. Croker, Jelena S. Bezbradica,* James E. Vince,†,‡ and Kate Schroder* The mammalian inhibitor of apoptosis proteins (IAPs) (2, 3). IAPs are degraded and/or inhibited upon exposure to are key regulators of cell death and inflammation. A genotoxic stress, proapoptotic stimuli (4), TNF superfamily major function of IAPs is to block the formation of a receptor ligation (5, 6), microbial infection (7), or the ap- Downloaded from cell death–inducing complex, termed the ripoptosome, plication of IAP antagonist compounds (8). Hereditary mu- which can trigger caspase-8–dependent apoptosis or tation can also reduce IAP expression, and in some cases, the caspase-independent necroptosis. Recent studies report clinical manifestation in humans resembles that of cryopyrin- that upon TLR4 or TNF receptor 1 (TNFR1) signaling associated periodic fever syndromes, which are driven by IL-1b (9). Consistent with this, LPS-TLR4 signaling in in macrophages, the ripoptosome can also induce http://www.jimmunol.org/ NLRP3 inflammasome formation and IL-1b matura- IAP-depleted macrophages induces ripoptosome-dependent tion. Whether neutrophils have the capacity to assemble caspase-8 activation, caspase-8–dependent IL-1b matura- a ripoptosome to induce cell death and inflammasome tion, and NLRP3 inflammasome signaling (6, 10, 11). Sim- activation during TLR4 and TNFR1 signaling is un- ilarly, TNF receptor 1 (TNFR1) ligation in XIAP-deficient clear. In this study, we demonstrate that murine dendritic cells activates caspase-8–dependent IL-1b matura- neutrophils can signal via TNFR1-driven ripoptosome tion and NLRP3 activation (12). Notably, TLR4-induced assembly to induce both cell death and IL-1b mat- NLRP3 activation upon IAP loss requires signaling by the TLR3/4 adaptor TRIF, which recruits RIPK3 and RIPK1 uration. However, unlike macrophages, neutrophils by guest on September 25, 2021 suppress TLR4-dependent cell death and NLRP3 inflam- through RIP homotypic interaction motif (RHIM) interac- masome activation during IAP inhibition via deficiencies tions to activate the ripoptosome (6, 10). When caspase-8 in the CD14/TRIF arm of TLR4 signaling. The Journal activity is suppressed, RIPK3 in turn activates the mixed of Immunology, 2018, 200: 3341–3346. lineage kinase domain–like protein (MLKL) to trigger nec- roptosis and drive NLRP3 inflammasome assembly (13). Neutrophils often exhibit specialized innate immune sig- he mammalian inhibitor of apoptosis proteins (IAPs), naling pathways to prolong their otherwise short lifespan (14, cellular IAP (cIAP)1, cIAP2, and X-linked IAP (XIAP), 15). In this study, we investigated whether the ripoptosome T are E3 ubiquitin ligases that inhibit caspases, apoptosis, induces neutrophils to undergo TNFR1- or TLR4-dependent and necroptosis. However, it is increasingly clear that IAPs are apoptosis, necroptosis, or NLRP3 inflammasome assembly. also critical regulators of proinflammatory signaling pathways (1). We demonstrate that deficiencies in the CD14/TRIF arm of Two studies reported that a loss of IAPs induces the for- the TLR4 signaling pathway enable LPS-stimulated neutro- mation of the ripoptosome death-inducing complex, com- phils to resist acute cell death and inflammasome activation prising the core components RIPK1, FADD, and caspase-8 upon IAP depletion. However, at later time points, IAP *Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The (Fellowship FT130100361 to K.S.). K.W.C. was supported by an ANZ Trustee Medical University of Queensland, St. Lucia, Queensland 4072, Australia; †Division of Inflam- Research Program, K.W.C. and D.B. were supported by The University of Queensland, mation, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria B.A.C. was supported by the American Asthma Foundation and National Institutes of 3052, Australia; ‡Department of Medical Biology, The University of Melbourne, Park- Health Grant 5R01HL124209-04, and M.G. was supported by the Israel Science x ville, Victoria 3050, Australia; Department of Clinical Microbiology and Immunology, Foundation (Grant 1416/15). { Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and Division Address correspondence and reprint requests to Associate Prof. Kate Schroder, Institute of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115 for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, 1K.E.L. and J.B.v.P. contributed equally to this work. Australia. E-mail address: [email protected] ORCIDs: 0000-0003-0471-6842 (K.E.L.); 0000-0002-7233-7177 (J.B.v.P.); 0000- The online version of this article contains supplemental material. 0003-0075-8893 (D.B.); 0000-0001-9518-1833 (M.G.); 0000-0002-0885- Abbreviations used in this article: cIAP, cellular IAP; Cp.A, compound A; FasL, Fas 3599 (B.A.C.); 0000-0001-9261-3805 (K.S.). ligand; IAP, inhibitor of apoptosis protein; LDH, lactate dehydrogenase; QVD, Q-VD- Received for publication December 4, 2017. Accepted for publication March 19, 2018. Oph; RHIM, RIP homotypic interaction motif; TNFR1, TNF receptor 1; XIAP, X-linked IAP. This work was supported by the National Health and Medical Research Council of Australia (Grant 1101405 and Fellowship 1141466 to J.E.V., Grants 1122240 and Ó 1023297 and Fellowship 1141131 to K.S.) and the Australian Research Council Copyright 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701620 3342 CUTTING EDGE: NEUTROPHILS RESIST TLR4-RIPK3–DEPENDENT CELL DEATH depletion sensitized neutrophils to LPS-induced autocrine 3 h to induce pro–IL-1b and NLRP3 expression, and IAPs TNF signaling, leading to caspase-8–dependent apoptosis and were then inhibited with Cp.A to induce ripoptosome IL-1b activation. If caspase-8 activity is blocked, IFN-g assembly. As expected, LPS stimulation suppressed basal priming rendered neutrophils sensitive to TNFR1-dependent neutrophil apoptosis but, surprisingly, did not enhance Cp.A- necroptosis and subsequent NLRP3 signaling. These findings mediated neutrophil death (Fig. 2A). In contrast, and con- highlight cell type specificity in the regulation of cell death sistent with previous reports (10, 11), LPS stimulation and inflammasome activation. enhanced Cp.A-mediated cell death in macrophages (Fig. 2B). Because LPS/Cp.A treatment did not elicit neutrophil death Materials and Methods (Fig. 2A), we hypothesized that IAP inhibition would be Mice similarly unable to drive caspase-8 and NLRP3 activation in 2 2 2 2 2 2 2 2 C57BL/6, Ice / (16), Tnfr1 / (17), Trif / (18), and Ripk3 / (19) mice LPS-primed neutrophils. We investigated the cleavage status were housed in specific pathogen-free facilities at The University of of caspase-8 and the caspase-8 substrate, Bid, in cells exposed Queensland and the Walter and Eliza Hall Institute. The animal ethics to LPS/Cp.A. Full-length caspase-8 and Bid levels were un- committees of these institutions approved all experimental protocols. affected by neutrophil treatment with Cp.A, regardless of Cell isolation, stimulation, and analysis LPS priming (Fig. 2C), whereas Fas ligand (FasL) triggered Mature bone marrow neutrophils and bone marrow–derived macrophages robust caspase-8 and Bid processing (Fig. 2C). In contrast, in were prepared from murine bone marrow as previously described (10, 15, 20). macrophages, Cp.A readily triggered caspase-8 activation and The purity of neutrophil isolation was 98–100%. Cells were stimulated with the subsequent cleavage of Bid, similar to FasL stimulation Downloaded
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