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The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation Through Modulation of NOTCH Signaling

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The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation Through Modulation of NOTCH Signaling The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation through Modulation of NOTCH Signaling This information is current as Almudena Ruiz-García, Susana López-López, José Javier of September 25, 2021. García-Ramírez, Victoriano Baladrón, María José Ruiz-Hidalgo, Laura López-Sanz, Ángela Ballesteros, Jorge Laborda, Eva María Monsalve and María José M. Díaz-Guerra J Immunol published online 29 August 2016 Downloaded from http://www.jimmunol.org/content/early/2016/08/27/jimmun ol.1600421 Supplementary http://www.jimmunol.org/content/suppl/2016/08/27/jimmunol.160042 http://www.jimmunol.org/ Material 1.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 25, 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 29, 2016, doi:10.4049/jimmunol.1600421 The Journal of Immunology The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation through Modulation of NOTCH Signaling Almudena Ruiz-Garcı´a,1 Susana Lo´pez-Lo´pez,1 Jose´ Javier Garcı´a-Ramı´rez, Victoriano Baladro´n, Marı´a Jose´ Ruiz-Hidalgo, Laura Lo´pez-Sanz, A´ ngela Ballesteros, Jorge Laborda, Eva Marı´a Monsalve, and Marı´a Jose´ M. Dı´az-Guerra The involvement of NOTCH signaling in macrophage activation by Toll receptors has been clearly established, but the factors and pathways controlling NOTCH signaling during this process have not been completely delineated yet. We have characterized the role of TSPAN33, a tetraspanin implicated in a disintegrin and metalloproteinase (ADAM) 10 maturation, during macrophage proin- flammatory activation. Tspan33 expression increases in response to TLR signaling, including responses triggered by TLR4, TLR3, Downloaded from and TLR2 activation, and it is enhanced by IFN-g. In this study, we report that induction of Tspan33 expression by TLR and IFN-g is largely dependent on NOTCH signaling, as its expression is clearly diminished in macrophages lacking Notch1 and Notch2 expression, but it is enhanced after overexpression of a constitutively active intracellular domain of NOTCH1. TSPAN33 is the member of the TspanC8 tetraspanin subgroup more intensely induced during macrophage activation, and its overexpression increases ADAM10, but not ADAM17, maturation. TSPAN33 favors NOTCH processing at the membrane by modulating ADAM10 and/or Presenilin1 activity, thus increasing NOTCH signaling in activated macrophages. Moreover, TSPAN33 modu- http://www.jimmunol.org/ lates TLR-induced proinflammatory gene expression, at least in part, by increasing NF-kB–dependent transcriptional activity. Our results suggest that TSPAN33 represents a new control element in the development of inflammation by macrophages that could constitute a potential therapeutic target. The Journal of Immunology, 2016, 197: 000–000. acrophages are key cells for the defense of the organism scribed that TLR signaling in macrophages increases expression against pathogens. Macrophages detect pathogens of different NOTCH receptors (5–7) and activates NOTCH sig- through molecular pattern recognition receptors, in naling. This process can modulate macrophage activation, favor- M by guest on September 25, 2021 particular TLR, which recognize several conserved microbial ing polarization toward an inflammatory phenotype, characterized structures. Signaling through these receptors represents a critical by higher IL-6, IL-12, and TNF-a production and enhanced cy- event in regulating macrophage activity, affecting cytokine and totoxicity (8, 9), mediated in part by increased NF-kB activity (10, chemokine production, receptor expression, cytotoxic activity, and 11). Indeed, Notch1 deficiency has been related to decreased in- cell migration (1, 2). Macrophages possess a remarkable plasticity flammation in different pathological models (12–15). and can change their functional phenotype in response to envi- NOTCH receptors are expressed on the cell surface as hetero- ronmental signals, becoming adapted to different situations by dimers of their N- and C-terminal fragments generated after fine-tuning their activity (3, 4). In this regard, it has been de- proteolytic cleavage at the trans-Golgi network (16, 17). These NOTCH receptor heterodimers adopt a protease-resistant confor- mation in their basal state, but after ligand binding to their ex- Facultad de Medicina, Centro Regional de Investigaciones Biome´dicas, Unidad de tracellular region, a hidden region is now exposed to an enzyme Biomedicina, Universidad de Castilla–La Mancha/Consejo Superior de Investiga- with a disintegrin and metalloprotease (ADAM) activity, such as ciones Cientificas, 02006 Albacete, Spain ADAM10, which upon cleaving at a site located at the extracel- 1 A.R.-G. and S.L.-L. contributed equally to this work. lular region of the membrane-bound, C-terminal moiety of the ORCIDs: 0000-0002-8348-3727 (J.J.G.-R.); 0000-0003-2508-8398 (M.J.R.-H.); NOTCH receptors creates a new substrate site that can be pro- 0000-0002-9210-838X (J.L.); 0000-0003-4933-4602 (E.M.M.); 0000-0003-3843- 3912 (M.J.M.D.-G.). cessed by a g-secretase complex. This, in turn, produces the re- Received for publication March 10, 2016. Accepted for publication August 8, 2016. lease of the NOTCH intracellular domains (NICD), which are translocated to the nucleus where they bind to the DNA-binding This work was supported by Instituto Carlos III, Ministerio de Economı´a y Com- petitividad, Spain Grants PI12/01546 and PI15/00991. protein RBP-J/CSL/CBF1 and other factors. This causes the as- Address correspondence and reprint requests to Dr. Marı´a Jose´ M. Dı´az-Guerra and sembly of an active transcriptional activation complex that drives Dr. Eva Marı´a Monsalve, Facultad de Medicina/Centro Regional de Investigaciones the expression of NOTCH target genes, in particular the HES and Biome´dicas, Universidad de Castilla–La Mancha, Avenida da Almansa 14, 02006 HEY families of transcription factors (18, 19). Albacete, Spain. E-mail addresses: [email protected] (M.J.M.D.-G.) and [email protected] (E.M.M.) Tetraspanins constitute a superfamily of 33 membrane proteins The online version of this article contains supplemental material. with four transmembrane regions, three short intracellular domains Abbreviations used in this article: ADAM, a disintegrin and metalloproteinase; COX, (two of them corresponding to the N- and C- terminal regions), and cyclooxygenase; Genot, genotyped; iNOS, inducible NO synthase; LTA, lipoteichoic a specific fold in the largest of the two extracellular regions, which acid; NICD, NOTCH intracellular domain; poly(I:C), polyinosinic-polycytidylic contains four or more cysteines in two or more CCG conserved acid; qPCR, quantitative PCR; shRNA, short hairpin RNA; WT, wild-type. sequences (20, 21). These proteins interact with each other and Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 with other integral membrane proteins to form microdomains on www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600421 2 TSPAN33 CONTROLS NOTCH SIGNALING IN MACROPHAGE ACTIVATION the plasma membrane, known as tetraspanin-enriched micro do- porter plasmids pNF-kB–luc, pRBP-J–luc, inducible NO synthase (iNOS)– mains (22–24). In these microdomains, tetraspanins have been luc, cyclooxygenase (COX)-2–luc, and pIFN-b–luc, used to detect found to interact with integrins and with Ig domain–containing NF-kB–, NOTCH-, iNOS-, COX-2–, and IFN-b–dependent transcription activities, respectively, have been previously described (32). pRLTK proteins, among others (25). A subgroup of tetraspanins, known as Renilla-expressing vector (Promega) was used as a control for transfection TSPANC8 owing to the eight cysteine residues present at their efficiency. pCMV6 (empty vector), pCMV6-Tspan33 (Tspan33 expression major extracellular loop, is composed of TSPAN5, 10, 14, 15, and vector), Sh-control (empty vector), Sh-Tspan33 (eBioscience), pLNCX2 17 and TSPAN33/PENUMBRA. TSPANC8 members are differ- (empty vector), pLNCX2-Notch1IC (intracellular Notch1 expression vec- tor), PCD2 (empty vector), and/or PCD2-Notch1 (full-length Notch1 ex- entially expressed in cells and tissues, and most of them interact pression vector) (33) were used together with the reporters. Cells were with ADAM10 and regulate its maturation and trafficking to the stimulated with 100 ng/ml LPS for 24 h after being transfected. Luciferase cell membrane (26–28). ADAM10 is a ubiquitous metalloprotease and Renilla activities were measured by using the Dual-Luciferase reporter that cleaves the extracellular regions of a large number of proteins, assay system (Promega) in a Monolight 3096 (BD Biosciences) following including NOTCH receptors, as previously described (29, 30). the manufacturers’ recommendations. For stable transfections, 3 3 106 Raw 264.7 cells were
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