title: Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus.
abstract: OBJECTIVE
  To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE).
  
  
  METHODS
  Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo.
  
  
  RESULTS
  In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFNgamma]-induced monokine), CXCL10 (IFNgamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA. IFNalpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes.
  
  
  CONCLUSIONS
  Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFNalpha-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype.
authors.affiliation: Heinrich-Heine University, Dusseldorf, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.forename: Franziska
authors.initials: F
authors.lastname: Winterberg
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Ingrida
authors.initials: I
authors.lastname: Lauceviciute
authors.forename: Juliane
authors.initials: J
authors.lastname: Rieker
authors.forename: Norbert J
authors.initials: NJ
authors.lastname: Neumann
authors.forename: Robert
authors.initials: R
authors.lastname: Kubitza
authors.forename: Michael
authors.initials: M
authors.lastname: Gombert
authors.forename: Erich
authors.initials: E
authors.lastname: Bünemann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wiesner
authors.forename: Petra
authors.initials: P
authors.lastname: Franken-Kunkel
authors.forename: Holger
authors.initials: H
authors.lastname: Kanzler
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Dieu-Nosjean
authors.forename: Ali
authors.initials: A
authors.lastname: Amara
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Percy
authors.initials: P
authors.lastname: Lehmann
authors.forename: Albert
authors.initials: A
authors.lastname: Zlotnik
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
mesh_terms: D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology*; D008178:Lupus Erythematosus, Cutaneous / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D011832:Radiation Injuries / Q000276:immunology*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins