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TLR Activation by Lipid Ligands the Cat Dander Protein Fel D 1

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TLR Activation by Lipid Ligands the Cat Dander Protein Fel D 1 Allergens as Immunomodulatory Proteins: The Cat Dander Protein Fel d 1 Enhances TLR Activation by Lipid Ligands This information is current as Jurgen Herre, Hans Grönlund, Heather Brooks, Lee of September 26, 2021. Hopkins, Lisa Waggoner, Ben Murton, Monique Gangloff, Olaniyi Opaleye, Edwin R. Chilvers, Kate Fitzgerald, Nick Gay, Tom Monie and Clare Bryant J Immunol 2013; 191:1529-1535; Prepublished online 22 July 2013; Downloaded from doi: 10.4049/jimmunol.1300284 http://www.jimmunol.org/content/191/4/1529 Supplementary http://www.jimmunol.org/content/suppl/2013/07/22/jimmunol.130028 http://www.jimmunol.org/ Material 4.DC1 References This article cites 35 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/191/4/1529.full#ref-list-1 Why The JI? Submit online. by guest on September 26, 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Allergens as Immunomodulatory Proteins: The Cat Dander Protein Fel d 1 Enhances TLR Activation by Lipid Ligands Jurgen Herre,*,† Hans Gro¨nlund,‡ Heather Brooks,† Lee Hopkins,† Lisa Waggoner,x Ben Murton,{ Monique Gangloff,{ Olaniyi Opaleye,{ Edwin R. Chilvers,* Kate Fitzgerald,x Nick Gay,{ Tom Monie,{ and Clare Bryant† Allergic responses can be triggered by structurally diverse allergens. Most allergens are proteins, yet extensive research has not revealed how they initiate the allergic response and why the myriad of other inhaled proteins do not. Among these allergens, the cat secretoglobulin protein Fel d 1 is a major allergen and is responsible for severe allergic responses. In this study, we show that similar to the mite dust allergen Der p 2, Fel d 1 substantially enhances signaling through the innate receptors TLR4 and TLR2. In contrast to Der p 2, however, Fel d 1 does not act by mimicking the TLR4 coreceptor MD2 and is not able to bind stably to the TLR4/MD2 complex in vitro. Fel d 1 does, however, bind to the TLR4 agonist LPS, suggesting that a lipid transfer mechanism may be involved in Downloaded from the Fel d 1 enhancement of TLR signaling. We also show that the dog allergen Can f 6, a member of a distinct class of lipocalin allergens, has very similar properties to Fel d 1. We propose that Fel d 1 and Can f 6 belong to a group of allergen immunomodulatory proteins that enhance innate immune signaling and promote airway hypersensitivity reactions in diseases such as asthma. The Journal of Immunology, 2013, 191: 1529–1535. http://www.jimmunol.org/ he innate immune system is intrinsically linked with al- acylated lipoproteins (8) and lipoteichoic acid (LTA). TLR5 rec- lergy. Pattern recognition receptors are involved in al- ognizes the bacterial protein flagellin (9, 10). Ligand recognition T lergen sampling, nonspecific allergen elimination, and the by TLRs then activates innate immune signaling pathways (11). maintenance of immune tolerance and homeostasis in response Both MD2 and Der p 2 belong to a small family of lipid-binding to allergens (1). An allergic response can be triggered by many proteins that have a b-sandwich or cup-type fold (12). These different stimuli, for example, grass pollen, animal dander, foods, proteins recognize lipid by intercalating their acyl chains into the insect venoms, pharmaceutical products, chemicals, latex, and hydrophobic core of the b-sandwich. Thus, one potential mech- metals (2). The exact mechanisms by which major allergens are anism by which Der p 2 enhances TLR4 signaling is to mimic recognized by the host are largely unknown, but recent work sug- MD2 by binding to TLR4. The Der p 2/TLR4 protein complex by guest on September 26, 2021 gests that TLRs play a crucial role in the response to two common may then signal similarly to MD2/TLR4 to activate innate im- allergens, house dust mite protein Der p 2 (3–5) and the metal mune signaling (4). In mouse models of allergic asthma the effects nickel (6). of Der p 2 are markedly reduced in TLR4 knockout mice and can Der p 2 is a lipid-binding protein that sensitizes ligand-induced be prevented in wild-type mice by administration of a TLR4 an- signaling through TLR4 and TLR2 (3, 4, 7). TLR4, in combination tagonist (7). House dust mite extracts carrying flagellin can induce with MD2 and CD14, recognizes bacterial LPSs, and TLR2, in a TLR5-dependent allergic responses in mice, although the molec- heterodimer with either TLR1 or TLR6, recognizes di- and tri- ular mechanism by which this occurs is unclear (5). Nickel sensi- tization in humans results from direct, lipid-independent activation of TLR4 by Ni2+. Receptor activation is dependent on the presence *Department of Medicine, University of Cambridge School of Medicine, Cambridge 2+ CB2 0QQ, United Kingdom; †Department of Veterinary Medicine, University of of two histidine residues, H456 and H458, which coordinate the Ni Cambridge, Cambridge CB3 0ES, United Kingdom; ‡Department of Clinical Neuro- atom (or other metal ions such as Co2+), promoting TLR4 dimer- science, Karolinska Institute, SE-171 76 Stockholm, Sweden; xDepartment of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and {Department ization and subsequent receptor activation. Murine TLR4 lacks of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom these histidines and consequently is not activated by nickel (6, 13). Received for publication January 31, 2013. Accepted for publication June 8, 2013. Another clinically important allergen is the cat dander protein This work was supported by Wellcome Trust Program Grant 081744/z/o6/z wt and Fel d 1, which is the most common cause of severe allergic res- Medical Research Council Grant G1000133 (to N.G. and C.B.). C.B. is supported by ponses to cats in humans (14). In contrast to Der p 2, this allergen a Biotechnology and Biological Sciences Research Council Research Development has an entirely a-helical structure (15) and is thus unlikely to act Fellowship. T.M. is supported by a Wellcome Trust Career Development Fellowship (Grant WT085090MA). J.H. was supported by an Academy of Medical Sciences as a mimetic of MD2. Fel d 1 can bind to the mannose receptor, Starter Grant for Clinical Lecturers. but immune signaling is not initiated following engagement of Address correspondence and reprint requests to Dr. Tom Monie or Dr. Clare Bryant, this receptor (16). Thus, the mechanism by which this protein Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cam- initiates an allergic response remains unclear. bridge CB2 1QW, U.K. (T.M.) or Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 OES, U.K. (C.B.). E-mail addresses: In this study we propose a mechanism by which Fel d 1 is [email protected] (T.M.) or [email protected] (C.B.) recognized by the host to activate immune signaling. Fel d 1 en- The online version of this article contains supplemental material. hances LPS- and LTA- but not flagellin-induced TLR signaling. Abbreviations used in this article: bFel d 1, baculovirus Fel d 1; BMDM, bone Unlike Der p 2, the mechanism for Fel d 1 enhancement of LPS- marrow–derived macrophage; IMP, immunomodulatory protein; LTA, lipoteichoic induced TLR4/MD2 activation does not involve the protein binding acid; rFel d 1, recombinant Fel d 1. to the TLRs, but it does require the presence of CD14. The dog Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 dander protein Can f 6 (17), a structurally distinct allergen from www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300284 1530 THE CAT ALLERGEN Fel d 1 ENHANCES TLR4 SIGNALING Fel d 1 and a member of the lipocalin family of allergens, also Transient transfection analysis enhances LPS-induced activation of TLR4 signaling, although, HEK293 cells were maintained in DMEM supplemented with 10% FCS, unlike Fel d 1, this protein has some MD2-independent effects. 2mML-glutamine, 100 U/ml penicillin, and 100 mg/ml streptomycin. We propose, therefore, that animal allergen proteins form a novel HEK293 cells were transfected as previously described (18). Briefly, cells 4 class of IMPs that enhance TLR signaling and hence play a were seeded at 3 3 10 /well in a 96-well plate and transiently transfected critical role in initiating allergic responses. The mechanism for 2 d later. TLR2, TLR4, TLR5, and CD14 were cloned into pcDNA3 and MD2 was subcloned into pEFIRES. Expression vectors containing cDNA TLR enhancement of signaling involves formation of a complex encoding TLR4, MD2, and CD14 (1 ng/well of each), a NF-kB tran- of bacterial lipids, such as LPS, with allergen and suggests that scription reporter vector encoding firefly luciferase (5 ng/well pNF-kB-luc; inhibitors of TLR2 and TLR4 may represent a new class of Clontech), and a constitutively active reporter vector encoding Renilla therapeutic compounds for the treatment of common allergic luciferase (5 ng/well phRG-TK; Promega), together with empty vector to ensure an optimal amount of DNA, were mixed with jetPEI (Polyplus diseases.
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