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Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing Β-1,3 Glucan Nida S

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Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing Β-1,3 Glucan Nida S Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing β-1,3 Glucan Nida S. Khan, Pia V. Kasperkovitz, Allison K. Timmons, Michael K. Mansour, Jenny M. Tam, Michael W. Seward, This information is current as Jennifer L. Reedy, Sravanthi Puranam, Marianela Feliu and of September 26, 2021. Jatin M. Vyas J Immunol published online 1 February 2016 http://www.jimmunol.org/content/early/2016/01/30/jimmun ol.1401545 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/01/30/jimmunol.140154 Material 5.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 26, 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 1, 2016, doi:10.4049/jimmunol.1401545 The Journal of Immunology Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing b-1,3 Glucan Nida S. Khan,*,† Pia V. Kasperkovitz,‡ Allison K. Timmons,* Michael K. Mansour,*,x Jenny M. Tam,* Michael W. Seward,* Jennifer L. Reedy,*,x Sravanthi Puranam,* Marianela Feliu,*,{ and Jatin M. Vyas*,x,‖ Dectin-1 and TLR9 play distinct roles in the recognition and induction of innate immune responses to Aspergillus fumigatus and Candida albicans. Dectin-1 is a receptor for the major fungal cell wall carbohydrate b-1,3 glucan that induces inflammatory cytokines and controls phagosomal maturation through spleen tyrosine kinase activation. TLR9 is an endosomal TLR that also modulates the inflammatory cytokine response to fungal pathogens. In this study, we demonstrate that b-1,3 glucan beads are sufficient to induce dynamic redistribution and accumulation of cleaved TLR9 to phagosomes. Trafficking of TLR9 to A. fumigatus and C. albicans phagosomes requires Dectin-1 recognition. Inhibition of phagosomal acidification blocks TLR9 accumulation on phagosomes con- Downloaded from taining b-1,3 glucan beads. Dectin-1–mediated spleen tyrosine kinase activation is required for TLR9 trafficking to b-1,3 glucan–, A. fumigatus–, and C. albicans–containing phagosomes. In addition, Dectin-1 regulates TLR9-dependent gene expression. Collectively, our study demonstrates that recognition of b-1,3 glucan by Dectin-1 triggers TLR9 trafficking to b-1,3 glucan–containing phag- osomes, which may be critical in coordinating innate antifungal defense. The Journal of Immunology, 2016, 196: 000–000. http://www.jimmunol.org/ nvasive fungal infections by Candida albicans and Asper- localization of TLRs is critical in recognition of microbial ligands, gillus fumigatus cause significant morbidity and mortality in downstream signaling, and self- versus non–self-discrimination (4). I immunocompromised patients despite the widespread use of TLR1, TLR2, TLR4, TLR5, and TLR6 are expressed at the plasma potent antifungal medications, suggesting that the immune system membrane and recognize bacterial and fungal cell wall components, plays a critical role in determining the outcome of the infection (1, whereas TLR3, TLR7, TLR8, and TLR9 are localized to the in- 2). Advances in the treatment of invasive fungal infections require tracellular compartments and recognize bacterial and viral nucleic elucidation of the molecular mechanisms that govern the host acids (5). A role for TLR9 has been implicated in host defense immune response. against A. fumigatus and C. albicans (6, 7). Activation of TLR9 Pathogen recognition by the host requires binding of highly homodimers in response to unmethylated CpG DNA requires pro- by guest on September 26, 2021 conserved microbial pathogen-associated molecular patterns epi- teolytic cleavage of its N-terminal ectodomain to generate a func- topes by germline-encoded pattern-recognition receptors includ- tional receptor, as well as a conformational change in the cytoplasmic ing TLRs and C-type lectin receptors (CLRs) (3). Subcellular signaling domains that is required for the recruitment of adaptor molecules (8–11). This N-terminal proteolytic cleavage of TLR9 is also required for recruitment to fungal-containing phagosomes *Division of Infectious Diseases, Department of Medicine, Massachusetts General (9, 12). Unlike other TLRs, macrophages lacking TLR9 show Hospital, Boston, MA 02114; †Biomedical Engineering and Biotechnology, Univer- sity of Massachusetts, Lowell, MA 01854; ‡Alnylam Pharmaceuticals, Cambridge, enhanced antifungal immunity (13). The molecular mechanisms MA 02142; xDepartment of Medicine, Harvard Medical School, Boston, MA governing regulation of TLR9 trafficking to fungal phagosomes 02115; {Nutrition and Metabolism, Boston University, Boston, MA 02118; ‖ remain to be determined. and Program in Immunology, Harvard Medical School, Boston, MA 02115 Dectin-1, a CLR, recognizes the carbohydrate b-1,3 glucan, ORCIDs: 0000-0002-5448-8289 (N.S.K.); 0000-0002-6364-9435 (P.V.K.); 0000- 0002-8412-315X (A.K.T.); 0000-0002-4813-6308 (M.W.S.); 0000-0002-9985-9565 which constitutes the major fungal cell wall component of mul- (J.M.V.). tiple pathogenic fungi including A. fumigatus, C. albicans, and Received for publication June 17, 2014. Accepted for publication January 3, 2016. Pneumocystis jirovecii (14–16). Dectin-1 plays an essential role in This work was supported by National Institutes of Health Grants 5R01 A1 092084 and pulmonary defense against A. fumigatus and chronic mucocuta- 1R01 A1 097519 and National Institutes of Health/National Institute of Allergy and neous Candida infections (15, 17). Upon ligand recognition, the Infectious Diseases Grants 1K08AI110655 (to M.K.M.), T32 A1007061-35 (to J.L.R.), and KL2 TR001100 (to J.L.R.). cytoplasmic ITAM motif of Dectin-1 is phosphorylated by Src family kinases, resulting in the recruitment of spleen tyrosine kinase The data presented in this article have been submitted to Gene Expression Omni- bus (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE73474) under acces- (Syk). Syk triggers an intracellular signaling cascade resulting in sion number GSE73474. proinflammatory cytokine production and induction of Th17 cells, Address correspondence and reprint requests to Dr. Jatin M. Vyas, Division of In- central to the control of mucosal fungal infections (18–20). fectious Diseases, Department of Medicine, Massachusetts General Hospital, 55 Fruit Dectin-1 interacts with TLR2 and TLR4, leading to a specific Street, Boston, MA 02114. E-mail address: [email protected] innate immune response against C. albicans (19, 21). Dectin-1 The online version of this article contains supplemental material. controls phagosome maturation (22), but its ability to regulate Abbreviations used in this article: BafA1, bafilomycin A1; CLR, C-type lectin re- ceptor; DIC, differential interference contrast; D1KO, Dectin-1–knockout; HK, heat- trafficking of intracellular TLRs has not been established. killed; IFI, IFN-inducible; PBS-T, PBS-0.01% Tween 20; PVDF, polyvinylidene We sought to define the role of Dectin-1 and Syk signaling on fluoride; RAW, RAW 264.7 macrophage-like cell line; Syk, spleen tyrosine kinase; TLR9 subcellular redistribution in APCs to phagosomes contain- TLR9KO, TLR9 knockout. ing pathogenic fungi. Using “fungal-like particles” that display Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 monodispersed b-1,3 glucan on a polystyrene platform (23), as www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401545 2 DECTIN-1 CONTROLS TLR9 RECRUITMENT well as C. albicans and A. fumigatus, our data show that the Surface fluorescence labeling of b-1,3 glucan beads and presence of b-1,3 glucan in phagosomes is sufficient for TLR9- CpG+IgG beads GFP recruitment. We further demonstrate that Dectin-1 controls b-1,3 Glucan beads and CpG+IgG beads were labeled for live cell imaging TLR9 trafficking to C. albicans and multiple A. fumigatus spore by mixing ∼5 3 106 beads with 30 mg N-hydroxysuccinimidyl ester Alexa stages. Endolysosomal acidification is required for TLR9 re- fluor dye (Invitrogen AF658 and AF647) in dimethylformamide for 1 h at cruitment to b-1,3 glucan beads-containing phagosomes. Using room temperature followed by three washes in PBS. Then labeled beads chemical inhibitors of Syk and the signaling-incompetent Dectin- were resuspended in PBS. 1, which are incapable of activating Syk, we demonstrate that Syk Confocal microscopy activation is required for TLR9 recruitment to b-1,3 glucan beads Macrophages were plated onto eight-chambered coverglass (LabTek; and fungal-containing phagosomes. Thermo Scientific, Rochester, NY) (13, 22, 23). Cells were incubated with stimuli at 37˚C for specified times. Coverglass were then mounted on Nikon Materials and Methods Ti-E inverted microscope equipped with CSU-X1 confocal spinning-disk head (Yokogawa, Sugarland, TX). A coherent, 4-W laser (Coherent, Santa Reagents Clara, CA) was used as an excitation light source to produce excitation Bafilomycin A1
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