{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:56:40Z","timestamp":1753891000947,"version":"3.41.2"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","award":["The Eye Charity (CSO project grant award: 3031-3032)"],"award-info":[{"award-number":["The Eye Charity (CSO project grant award: 3031-3032)"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000882","name":"University of Aberdeen","doi-asserted-by":"publisher","award":["Development trust (saving sight in Grampian RG-12663 and RG-14251"],"award-info":[{"award-number":["Development trust (saving sight in Grampian RG-12663 and RG-14251"]}],"id":[{"id":"10.13039\/501100000882","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["217093\/Z\/19\/Z"],"award-info":[{"award-number":["217093\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MRV0109721"],"award-info":[{"award-number":["MRV0109721"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900833"],"award-info":[{"award-number":["81900833"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Herpes stromal keratitis (HSK) is a blinding corneal disease caused by herpes simplex virus-1 (HSV-1), a common pathogen infecting most of the world\u2019s population. Inflammation in HSK is chemokine-dependent, particularly CXCL10 and less so the CC chemokines. The atypical chemokine receptor-2 (ACKR2) is a decoy receptor predominantly for pro-inflammatory CC chemokines, which regulates the inflammatory response by scavenging inflammatory chemokines thereby modulating leukocyte infiltration. Deletion of ACKR2 exacerbates and delays the resolution of the inflammatory response in most models. ACKR2 also regulates lymphangiogenesis and mammary duct development through the recruitment of tissue-remodeling macrophages. Here, we demonstrate a dose-dependent upregulation of ACKR2 during corneal HSV-1 infection. At an HSV inoculum dose of 5.4 x 10<jats:sup>5<\/jats:sup>pfu, but not at higher dose, ACKR2 deficient mice showed prolonged clinical signs of HSK, increased infiltration of leukocytes and persistent corneal neovascularization. Viral clearance and T cell activation were similar in ACKR2<jats:sup>-\/-<\/jats:sup>and wild type mice, despite a transient diminished expression of CD40 and CD86 in dendritic cells. The data suggest that ACKR2 fine-tunes the inflammatory response and the level of neovascularization in the HSK.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1054260","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T08:14:41Z","timestamp":1669623281000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The atypical chemokine receptor-2 fine-tunes the immune response in herpes stromal keratitis"],"prefix":"10.3389","volume":"13","author":[{"given":"Tian","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian","family":"Schuette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Christofi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John V.","family":"Forrester","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard J.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Kuffova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/ICO.0000000000002122","article-title":"A review of the literature on the global epidemiology of corneal blindness","volume":"38","author":"Porth","year":"2019","journal-title":"Cornea"},{"key":"B2","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.preteyeres.2012.08.002","article-title":"Herpes keratitis","volume":"32","author":"Rowe","year":"2013","journal-title":"Prog Retin Eye Res"},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.138.3.884","article-title":"Role of NK cells in protection of mice against herpes simplex virus-1 infection","volume":"138","author":"Rager-Zisman","year":"1987","journal-title":"J Immunol"},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.158.3.1383","article-title":"On the essential involvement of neutrophils in the immunopathologic disease: herpetic stromal keratitis","volume":"158","author":"Thomas","year":"1997","journal-title":"J Immunol"},{"key":"B5","article-title":"Role of macrophages in restricting herpes simplex virus type 1 growth after ocular infection","volume":"41","author":"Cheng","year":"2000","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.67.6.3404-3408.1993","article-title":"Herpetic stromal keratitis in the reconstituted scid mouse model","volume":"67","author":"Mercadal","year":"1993","journal-title":"J Virol"},{"key":"B7","article-title":"Herpetic stromal keratitis: an immunopathologic disease mediated by CD4+ T lymphocytes","volume":"33","author":"Doymaz","year":"1992","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00766","article-title":"Pathogenesis of herpes stromal keratitis: Immune inflammatory response mediated by inflammatory regulators","volume":"11","author":"Wang","year":"2020","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1462399404007604","article-title":"Herpetic eye disease: immunopathogenesis and therapeutic measures","volume":"6","author":"Deshpande","year":"2004","journal-title":"Expert Rev Mol Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.eye.6701968","article-title":"The value of corneal transplantation in reducing blindness","volume":"19","author":"Garg","year":"2005","journal-title":"Eye (Lond)."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-17894","article-title":"High-risk corneal graft rejection in the setting of previous corneal herpes simplex virus (HSV)-1 infection","volume":"57","author":"Kuffova","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nri3544","article-title":"Immune regulation by atypical chemokine receptors","volume":"13","author":"Nibbs","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201948374","article-title":"Analysis of lung stromal expression of the atypical chemokine receptor ACKR2 reveals unanticipated expression in murine blood endothelial cells","volume":"50","author":"Hansell","year":"2020","journal-title":"Eur J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607514104","article-title":"Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6","volume":"104","author":"Martinez de la Torre","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.11.8170-a","article-title":"Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1","volume":"181","author":"McKimmie","year":"2008","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ni1182","article-title":"The chemokine receptor D6 limits the inflammatory response in vivo","volume":"6","author":"Jamieson","year":"2005","journal-title":"Nat Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200526114","article-title":"Increased inflammation in mice deficient for the chemokine decoy receptor D6","volume":"35","author":"Martinez de la Torre","year":"2005","journal-title":"Eur J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002395RR","article-title":"ACKR2 limits skin fibrosis and hair loss through IFN-beta","volume":"35","author":"Butenko","year":"2021","journal-title":"FASEB J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.11.013","article-title":"The atypical chemokine receptor 2 limits renal inflammation and fibrosis in murine progressive immune complex glomerulonephritis","volume":"93","author":"Bideak","year":"2018","journal-title":"Kidney Int"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.09.016","article-title":"The atypical chemokine receptor 2 limits progressive fibrosis after acute ischemic kidney injury","volume":"189","author":"Lux","year":"2019","journal-title":"Am J Pathol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-344044","article-title":"D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion","volume":"118","author":"Lee","year":"2011","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-425314","article-title":"An analysis of the function and expression of D6 on lymphatic endothelial cells","volume":"121","author":"McKimmie","year":"2013","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201488887","article-title":"The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density","volume":"33","author":"Lee","year":"2014","journal-title":"EMBO J"},{"key":"B24","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1242\/dev.139733","article-title":"Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland","volume":"144","author":"Wilson","year":"2017","journal-title":"Development"},{"key":"B25","doi-asserted-by":"publisher","first-page":"dev187815","DOI":"10.1242\/dev.187815","article-title":"Chemokine receptors coordinately regulate macrophage dynamics and mammary gland development","volume":"147","author":"Wilson","year":"2020","journal-title":"Development"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-018-4070-1","article-title":"The atypical chemokine receptor-2 does not alter corneal graft survival but regulates early stage of corneal graft-induced lymphangiogenesis","volume":"256","author":"Yu","year":"2018","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5A0414-233RR","article-title":"Chemokine decoy receptor D6 mimicking trap (D6MT) prevents allosensitization and immune rejection in murine corneal allograft model","volume":"97","author":"Choi","year":"2015","journal-title":"J Leukoc Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.045","article-title":"Lymphangiogenesis: Molecular mechanisms and future promise","volume":"140","author":"Tammela","year":"2010","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"17","DOI":"10.4049\/jimmunol.177.1.17","article-title":"Cutting edge: the silent chemokine receptor D6 is required for generating T cell responses that mediate experimental autoimmune encephalomyelitis","volume":"177","author":"Liu","year":"2006","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.90","article-title":"The atypical chemokine receptor ACKR2 suppresses Th17 responses to protein autoantigens","volume":"93","author":"Hansell","year":"2015","journal-title":"Immunol Cell Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070608","article-title":"Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in mycobacterium tuberculosis infection","volume":"205","author":"Di Liberto","year":"2008","journal-title":"J Exp Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-388082","article-title":"Control of murine Ly6C(high) monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6","volume":"119","author":"Savino","year":"2012","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802802","article-title":"The atypical chemokine receptor D6 contributes to the development of experimental colitis","volume":"182","author":"Bordon","year":"2009","journal-title":"J Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1136\/gut.2009.183772","article-title":"The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6","volume":"59","author":"Vetrano","year":"2010","journal-title":"Gut"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200606-839OC","article-title":"The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity","volume":"175","author":"Whitehead","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e03-09-0634","article-title":"The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines","volume":"15","author":"Weber","year":"2004","journal-title":"Mol Biol Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1182\/blood-2007-08-108316","article-title":"Regulation of D6 chemokine scavenging activity by ligand- and Rab11-dependent surface up-regulation","volume":"112","author":"Bonecchi","year":"2008","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"7261980","DOI":"10.1155\/2017\/7261980","article-title":"Understanding the role of chemokines and cytokines in experimental models of herpes simplex keratitis","volume":"2017","author":"Azher","year":"2017","journal-title":"J Immunol Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3319","article-title":"An innate antiviral pathway acting before interferons at epithelial surfaces","volume":"17","author":"Iversen","year":"2016","journal-title":"Nat Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.virol.2017.02.022","article-title":"CXCL9 compensates for the absence of CXCL10 during recurrent herpetic stromal keratitis","volume":"506","author":"Tajfirouz","year":"2017","journal-title":"Virology"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2011.03.006","article-title":"CXCL10 expressing hematopoietic-derived cells are requisite in defense against HSV-1 infection in the nervous system of CXCL10 deficient mice","volume":"234","author":"Wuest","year":"2011","journal-title":"J Neuroimmunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.77.18.10037-10046.2003","article-title":"Effect of anti-CXCL10 monoclonal antibody on herpes simplex virus type 1 keratitis and retinal infection","volume":"77","author":"Carr","year":"2003","journal-title":"J Virol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.3390\/cancers13051054","article-title":"CXCL10 is an agonist of the CC family chemokine scavenger receptor ACKR2\/D6","volume":"13","author":"Chevigne","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800131","article-title":"The atypical chemokine receptor Ackr2 constrains NK cell migratory activity and promotes metastasis","volume":"201","author":"Hansell","year":"2018","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2013.06.003","article-title":"Type I interferon and lymphangiogenesis in the HSV-1 infected cornea - are they beneficial to the host","volume":"36","author":"Bryant-Hudson","year":"2013","journal-title":"Prog Retin Eye Res"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4161\/21624011.2014.955337","article-title":"Atypical chemokine receptor 2: a brake against kaposi's sarcoma aggressiveness","volume":"3","author":"Bonecchi","year":"2014","journal-title":"Oncoimmunology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0202","article-title":"ERK-dependent downregulation of the atypical chemokine receptor D6 drives tumor aggressiveness in kaposi sarcoma","volume":"2","author":"Savino","year":"2014","journal-title":"Cancer Immunol Res"},{"key":"B48","doi-asserted-by":"publisher","first-page":"108363","DOI":"10.1016\/j.exer.2020.108363","article-title":"Corneal neovascularization","volume":"202","author":"Nicholas","year":"2021","journal-title":"Exp Eye Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091385","article-title":"VEGF-a expression by HSV-1-infected cells drives corneal lymphangiogenesis","volume":"207","author":"Wuest","year":"2010","journal-title":"J Exp Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0898","article-title":"CD8 T cells mediate transient herpes stromal keratitis in CD4-deficient mice","volume":"47","author":"Lepisto","year":"2006","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.3.1353","article-title":"Cross presentation of antigen on MHC class II via the draining lymph node after corneal transplantation in mice","volume":"180","author":"Kuffova","year":"2008","journal-title":"J Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1080\/08977190801932550","article-title":"A system for quantifying the patterning of the lymphatic vasculature","volume":"25","author":"Shayan","year":"2007","journal-title":"Growth Factors"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.12.7575","article-title":"Protective and pathological roles of virus-specific and bystander CD8+ T cells in herpetic stromal keratitis","volume":"173","author":"Banerjee","year":"2004","journal-title":"J Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00496-10","article-title":"Delaying the expression of herpes simplex virus type 1 glycoprotein b (gB) to a true late gene alters neurovirulence and inhibits the gB-CD8+ T-cell response in the trigeminal ganglion","volume":"84","author":"Ramachandran","year":"2010","journal-title":"J Virol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1054260\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T11:45:18Z","timestamp":1678794318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1054260\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,28]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2022.1054260"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1054260","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2022,11,28]]},"article-number":"1054260"}}