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OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- Α Release from Human CCR2 + Inflammatory Monocytes

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OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- Α Release from Human CCR2 + Inflammatory Monocytes OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- α Release from Human CCR2 + Inflammatory Monocytes This information is current as Alexander D. Barrow, Yaseelan Palarasah, Mattia Bugatti, of September 25, 2021. Alex S. Holehouse, Derek E. Byers, Michael J. Holtzman, William Vermi, Karsten Skjødt, Erika Crouch and Marco Colonna J Immunol 2015; 194:3317-3326; Prepublished online 25 February 2015; Downloaded from doi: 10.4049/jimmunol.1402289 http://www.jimmunol.org/content/194/7/3317 Supplementary http://www.jimmunol.org/content/suppl/2015/02/24/jimmunol.140228 http://www.jimmunol.org/ Material 9.DCSupplemental References This article cites 40 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/194/7/3317.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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology OSCAR Is a Receptor for Surfactant Protein D That Activates TNF-a Release from Human CCR2+ Inflammatory Monocytes Alexander D. Barrow,* Yaseelan Palarasah,† Mattia Bugatti,‡ Alex S. Holehouse,x,{ Derek E. Byers,‖ Michael J. Holtzman,‖ William Vermi,*,‡ Karsten Skjødt,† Erika Crouch,* and Marco Colonna* Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D–encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (OSCAR) Downloaded from within the SP-D collagenous domain. An OSCAR-Fc fusion protein specifically bound to the collagenous region of recombinant SP-D and captured native SP-D from human bronchoalveolar lavage. OSCAR localized in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we found OSCAR on the surface of interstitial lung and blood CCR2+ inflammatory monocytes, which secreted TNF-a when exposed to SP-D in an OSCAR-dependent fashion. OSCAR and SP-D did not exclusively colocalize in lung, as they were also highly expressed in atherosclerotic plaques of human aorta, supporting a role for this interaction in atherosclerosis. Our results identify the OSCAR:SP-D interaction as a potential therapeutic target in http://www.jimmunol.org/ chronic inflammatory diseases of the lung as well as other diseases involving tissue accumulation of SP-D, infiltration of inflam- matory monocytes, and release of TNF-a. The Journal of Immunology, 2015, 194: 3317–3326. urfactant protein D (SP-D) is a member of the collagenous dues (Cys15 and Cys20). Multimeric SP-D dodecamers can be lectins (collectins), which provide a first line of humoral formed through N-terminal disulfide bonding of trimeric SP-D S innate immune defense (1–3). The collectin family also monomers. Within the collectin family, the formation of dodeca- includes, but is not limited to, mannan-binding lectin (MBL) and mers is unique to SP-D, which can be observed as the charac- surfactant protein A (SP-A). Collectins are soluble proteins that teristic cruciform structures by electron microscopy (5). The by guest on September 25, 2021 are structurally characterized by an N-terminal collagenous re- collectin family is expressed in different mucosae and plays an gion, a flexible coiled coil neck region, and a C-terminal carbo- important tissue-specific role in the innate immune response (4). hydrate recognition domain (CRD), which binds various sugars in SP-D is predominantly secreted by alveolar type II epithelial a calcium-dependent fashion (4). The hydrophobic N-terminal cells, but is also produced outside of the lung, in the gastrointestinal region of the SP-D polypeptide encodes two cysteine (Cys) resi- and genital mucosae, salivary glands, prostate, kidney, pancreas, skin, and endothelial cells (6). SP-D can act as a pattern recog- nition receptor through binding of the CRD to evolutionary con- *Department of Pathology and Immunology, Washington University School of Med- icine, St. Louis, MO 63110; †Department of Cancer and Inflammation, University of served glycolipids and glycoproteins associated with infectious Southern Denmark, 5000 Odense, Denmark; ‡Department of Molecular and Trans- agents, such as LPS from certain bacterial species or viral enve- lational Medicine, Section of Pathology, School of Medicine, University of Brescia, lope glycoproteins. SP-D can thus opsonize, neutralize, and ag- Brescia 25123, Italy; xDivision of Biology and Biomedical Sciences, Washington University, St. Louis, MO 63110; {Center for Biological Systems Engineering, Wash- glutinate infectious microorganisms predisposing to elimination ington University, St. Louis, MO 63130; and ‖Division of Pulmonary and Critical by phagocytes. In the lung, SP-D also plays an important ho- Care Medicine, Department of Medicine, Washington University School of Medi- meostatic role through CRD-dependent scavenging of surfactant cine, St. Louis, MO 63110 phospholipids by alveolar macrophages (7, 8). SP-D–deficient ORCID: 0000-0002-4155-5729 (A.S.H.). (Sftpd2/2) mice developed accumulation of surfactant phospho- Received for publication September 10, 2014. Accepted for publication January 24, 2015. lipids in the lungs, as well as infiltration of monocytes and the proinflammatory activation of alveolar macrophages, leading to This work was supported by National Institutes of Health Grant 5R01HL097805 (to M.C.) and a Marie Curie International Outgoing Fellowship (to A.D.B.). chronic inflammation, emphysema, and fibrosis (9, 10). Correction 2/2 Address correspondence and reprint requests to Prof. Marco Colonna at the current of some, but not all, of the pulmonary abnormalities in Sftpd address: BJC Institute of Health at Washington University, 425 South Euclid, Campus mice required the transgenic expression of SP-D with an intact Box 8118, St. Louis, MO 63110. E-mail address: [email protected] collagenous domain (11). SP-D–deficient children were suscepti- The online version of this article contains supplemental material. ble to more frequent pneumonias, and long-term outcome was Abbreviations used in this article: BAL, bronchoalveolar lavage; COPD, chronic worse than SP-D–sufficient control children (12). obstructive pulmonary disease; C1q, complement component 1q; CRD, carbohy- drate recognition domain; Cys, cysteine; ILT, Ig-like transcript; LAIR, leukocyte- Human SFTPD genotype can influence the assembly, concen- associated Ig-like receptor; MBL, mannan-binding lectin; NCRD, neck CRD; tration, and biological function of SP-D in vivo (13). Interestingly, OSCAR, osteoclast-associated receptor; SP-A, surfactant protein A; SP-D, surfac- polymorphisms in SFTPD have been associated with susceptibil- tant protein D; TREM, triggering receptor expressed on myeloid cells. ity to chronic and infectious lung diseases, such as chronic ob- Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 structive pulmonary disease (COPD) (14, 15), emphysema (16), www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402289 3318 OSCAR IS A NOVEL MONOCYTE SP-D RECEPTOR pneumococcal lung disease (17), and tuberculosis (18), and may cDNA with Platinum Pfx DNA Polymerase (Invitrogen) using the fol- even influence clinical outcome following lung transplantation lowing forward, 59-CATCCTCGAGCAGGAGGAAGATCTGCCCAG-39 (19). Serum SP-D levels have been associated with lung function and reverse, 59-GAATTCTAGAATGCTCAGCTTTCAGGCCTTG-39 primers (XhoI and XbaI restriction sites underlined). XhoI- and XbaI- or health status in patients with severe COPD (20). SFTPD ge- restricted PCR products were cloned into the Signal Ig plus vector, notype has also been associated with inflammatory bowel dis- whichencodedtheLAIR-1ectodomaininframewithhumanIgG1Fc. eases, such as Crohn’s disease and ulcerative colitis (21). SP-D is Cloning and expression of Ig-like transcript (ILT)-1, -3, and -7 and trig- also produced by vascular endothelial cells and has been impli- gering receptor expressed on myeloid cells (TREM)-1 and -2 Fc-fusion 2 2 proteins were as described (28). cated in lipid homeostasis and vascular lipid deposition. Sftpd / mice were protected from diet-induced atherosclerosis (22), Cell culture, expression, and purification of recombinant whereas a polymorphism of SFTPD has been associated with Fc-fusion proteins coronary artery disease (23). These data suggest an important role The 293T were transiently transfected with 48 mg plasmid DNA/10-cm dish for SP-D in regulating pulmonary homeostasis in addition to roles using Lipofectamine 2000 diluted in Optimem (both
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