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IRF8 Regulates Gram-Negative Bacteria–Mediated NLRP3 Inflammasome Activation and Cell Death

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IRF8 Regulates Gram-Negative Bacteria–Mediated NLRP3 Inflammasome Activation and Cell Death IRF8 Regulates Gram-Negative Bacteria− Mediated NLRP3 Inflammasome Activation and Cell Death This information is current as Rajendra Karki, Ein Lee, Bhesh R. Sharma, Balaji Banoth of September 25, 2021. and Thirumala-Devi Kanneganti J Immunol published online 23 March 2020 http://www.jimmunol.org/content/early/2020/03/20/jimmun ol.1901508 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/03/20/jimmunol.190150 Material 8.DCSupplemental http://www.jimmunol.org/ 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 by guest on September 25, 2021 *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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 23, 2020, doi:10.4049/jimmunol.1901508 The Journal of Immunology IRF8 Regulates Gram-Negative Bacteria–Mediated NLRP3 Inflammasome Activation and Cell Death Rajendra Karki,*,1 Ein Lee,*,†,1 Bhesh R. Sharma,*,1 Balaji Banoth,* and Thirumala-Devi Kanneganti* Inflammasomes are intracellular signaling complexes that are assembled in response to a variety of pathogenic or physiologic stimuli to initiate inflammatory responses. Ubiquitously present LPS in Gram-negative bacteria induces NLRP3 inflammasome activation that requires caspase-11. We have recently demonstrated that IFN regulatory factor (IRF) 8 was dispensable for caspase-11–mediated NLRP3 inflammasome activation during LPS transfection; however, its role in Gram-negative bacteria– mediated NLRP3 inflammasome activation remains unknown. In this study, we found that IRF8 promotes NLRP3 inflammasome activation in murine bone marrow–derived macrophages (BMDMs) infected with Gram-negative bacteria such as Citrobacter rodentium, Escherichia coli,orPseudomonas aeruginosa mutant strain DpopB. Moreover, BMDMs deficient in IRF8 showed Downloaded from substantially reduced caspase-11 activation and gasdermin D cleavage, which are required for NLRP3 inflammasome activation. Mechanistically, IRF8-mediated phosphorylation of IRF3 was required for Ifnb transcription, which in turn triggered the caspase- 11–dependent NLRP3 inflammasome activation in the infected BMDMs. Overall, our findings suggest that IRF8 promotes NLRP3 inflammasome activation during infection with Gram-negative bacteria. The Journal of Immunology, 2020, 204: 000–000. nflammasomes are molecular platforms that are assembled caspase 4/5 (in humans) and occurs strictly in response to the http://www.jimmunol.org/ in response to a variety of pathogenic or physiologic stimuli Gram-negative bacteria–derived PAMP LPS (3, 4). Cytosolic LPS I to initiate activation of inflammatory caspases, resulting in activates caspase-11, leading to the cleavage of gasdermin D cytokine production and cell death. Although some inflammasomes (GSDMD), which is sufficient to induce pyroptosis (5, 6). Processing have defined ligands, the NLRP3 inflammasome serves as a global of the proinflammatory cytokines IL-1b and IL-18 is still dependent sensor of pathogen-associated molecular patterns (PAMPs) and on subsequent NLRP3 inflammasome activation downstream of damage-associated molecular patterns (1). The recognition of caspase-11 activation. Thus, successful cytoplasmic delivery of PAMPs and damage-associated molecular patterns by NLRP3 LPS via intracellular infection with Gram-negative bacteria, de- requires two steps: priming and activation. The priming step leads livery of bacterial outer membrane vesicles, or direct LPS trans- to the transcriptional upregulation of NLRP3 and pro–IL-1b;the fection is a fundamental requirement for noncanonical NLRP3 by guest on September 25, 2021 activation step then leads to NLRP3 oligomerization and initiates inflammasome activation (7). the assembly of the NLRP3 inflammasome (2). However, non- IFN signaling has been recognized as a central regulator of canonical NLRP3 activation requires caspase-11 (in mice) or inflammasome activation during bacterial infections. In particular, type I IFN priming is required for noncanonical NLRP3 inflam- masome activation during infection with Gram-negative bacteria (8). *Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN We and others have previously discovered that the TLR4–TRIF axis 38105; and †Integrated Biomedical Sciences Program, University of Tennessee regulates caspase-11 expression and noncanonical NLRP3 inflam- Health Science Center, Memphis, TN 38163 masome activation during infection with enteropathogens such as 1 R.K., E.L., and B.R.S. contributed equally. Escherichia coli and Citrobacter rodentium (9–11). However, bone ORCIDs: 0000-0003-3609-833X (B.R.S.); 0000-0002-6395-6443 (T.-D.K.). marrow–derived macrophages (BMDMs) deficient in TRIF or the Received for publication December 20, 2019. Accepted for publication February 24, IFN-a/b receptor (IFNAR) undergo pyroptosis at a rate similar to 2020. that of wild-type (WT) BMDMs transfected with LPS, suggesting This work was supported by funding from the National Institutes of Health Grants that TRIF/IFN signaling is dispensable for noncanonical NLRP3 CA163507, AR056296, AI124346, and AI101935 and by American Lebanese Syrian Associated Charities (to T.‐D.K.). inflammasome activation by LPS transfection (4). IFN-inducible R.K. and T.-D.K. conceptualized the study; R.K., E.L., and B.R.S. designed the guanylate-binding proteins (GBPs) and immunity-related GTPase methodology; R.K., E.L., B.R.S., and B.B. performed the experiments; R.K., E.L., family member b10 (IRGB10) also contribute to noncanonical B.R.S., and B.B. conducted the analysis; and R.K. and T.-D.K. wrote the manuscript NLRP3 inflammasome activation by liberating Gram-negative with input from all authors. T.-D.K. acquired the funding and provided overall supervision. bacteria from pathogen-containing vacuoles and disrupting the Address correspondence and reprint requests to Dr. Thirumala-Devi Kanneganti, structural integrity of the bacteria. This process ultimately St. Jude Children’s Research Hospital, MS #351, 570 St. Jude Place, Suite E7004, releases LPS into the cytoplasm, allowing detection by caspase-11 Memphis, TN 38105-2794. E-mail address: [email protected] (12–14). The online version of this article contains supplemental material. Type I IFN induction in dendritic cells is greatly enhanced by Abbreviations used in this article: ASC, apoptosis-associated speck-like protein con- IFN regulatory factor (IRF) 8 via the prolongation of recruitment taining a caspase activation and recruitment domain; BMDM, bone marrow–derived macrophage; CST, Cell Signaling Technology; GBP, guanylate-binding protein; of basal transcription machinery to the IFN promoters during viral GSDMD, gasdermin D; IRF, IFN regulatory factor; IRGB10, immunity-related infection (15). Similarly, the concerted activation of IRF8 and GTPase family member b10; LB, Luria-Bertani; MOI, multiplicity of infection; IRF3 in human monocytes regulates IFN-b production in response PAMP, pathogen-associated molecular pattern; t, total; WT, wild-type. to LPS or viral infection (16), suggesting IRF8 is a critical Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 contributor to the rapid and abundant type I IFN production in www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901508 2 REGULATION OF CASPASE-11–MEDIATED NLRP3 INFLAMMASOME BY IRF8 immune cells. Our recent study found that IRF8 is not required (catalog no. 4302; CST), anti–p-IKKε (catalog no. 8766; CST), anti– for noncanonical NLRP3 inflammasome activation during LPS t-IKKε (catalog no. 3416; CST), anti-GAPDH (catalog no. 5174; CST), transfection (17). However, given that IRF8 plays an impor- anti-IRF1 (catalog no. 8478; CST), anti-GBP2 (catalog no. 27299-1-AP; b Proteintech), anti-GBP5 (catalog no. 13220-1-AP; Proteintech), anti–p-STAT1 tant role in IFN- production, we hypothesized that IRF8 (catalog no. 7649; CST), anti–t-STAT1 (catalog no. 14994; CST), anti–caspase-3 would be required for Gram-negative bacteria–mediated NLRP3 (catalog no. 9662; CST), anti–cleaved caspase-3 (catalog no. 9661; CST), inflammasome activation. anti–caspase-7 (catalog no. 9492; CST), anti–cleaved caspase-7 (catalog no. 9491; CST), anti–caspase-8 (AG-20T-0138-C100; AdipoGen Life Sciences), anti–cleaved caspase-8 (catalog no. 8592; CST), anti-IRGB10 Materials and Methods rabbit serum raised against recombinant full-length IRGB10 (1:10,000 Mice dilution) (21), and anti-IRF8 (catalog no. A5798; ABclonal). Membranes 2/2 2/2 2/2 2/2 2/2 were then washed and incubated with the appropriate HRP-conjugated Irf8 (17), Stat1 (18), Casp11 (14), Irgb10 (14), and Nlrp3 secondary Abs (1:5000 dilution; Jackson ImmunoResearch Laboratories, (14) mice have been described previously. Six-to-eight-week-old male and anti-rabbit [111-035-047], anti-mouse [315-035-047], and anti-rat [112-035-003]) female mice were used in this study. Mice were bred at St. Jude Children’s
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