title: Spread of Psoriasiform Inflammation to Remote Tissues Is Restricted by the Atypical Chemokine Receptor ACKR2.
abstract: Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis-associated atypical chemokine receptor 2 (ACKR2) binds, internalizes and degrades most proinflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion. Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays, and the imiquimod-induced model of psoriasiform skin inflammation. Localized inflammation and IFN-γ together up-regulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases.
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK.
authors: Kave
authors: K
authors: Shams
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK.
authors: Gillian J
authors: GJ
authors: Wilson
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK.
authors: Mark
authors: M
authors: Singh
authors: Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Ellen H
authors: EH
authors: van den Bogaard
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK.
authors: Michelle L
authors: ML
authors: Le Brocq
authors: Glasgow Royal Infirmary, 84 Castle Street, Glasgow, UK.
authors: Susan
authors: S
authors: Holmes
authors: Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Joost
authors: J
authors: Schalkwijk
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK; Department of Dermatology, Lauriston Building, Edinburgh, UK.
authors: A David
authors: AD
authors: Burden
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK; Virus Host Interaction Team, Leeds Institute of Cancer and Pathology, University of Leeds, St James' University Hospital, Leeds, UK. Electronic address: c.s.mckimmie@leeds.ac.uk.
authors: Clive S
authors: CS
authors: McKimmie
authors: Chemokine Research Group, Institute of Infection, Immunity and Inflammation, 120 University Place, University of Glasgow, Glasgow, UK. Electronic address: gerard.graham@glasgow.ac.uk.
authors: Gerard J
authors: GJ
authors: Graham
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001707:Biopsy, Needle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D000077271:Imiquimod; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011897:Random Allocation; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D018709:Statistics, Nonparametric; D015854:Up-Regulation; D000097628:Chemokine Receptor D6
chemical_list: D000634:Aminoquinolines; D000077271:Imiquimod; D019707:Receptors, Chemokine; C515708:ACKR2 protein, human; D000097628:Chemokine Receptor D6