title: CCR5 chemokine receptor mediates recruitment of MHC class II-positive Langerhans cells in the mouse corneal epithelium.
abstract: OBJECTIVE
  To characterize the chemokines and chemokine receptors that mediate the effect of proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, on the recruitment of MHC class II(+) Langerhans cells (LCs) in the corneal epithelium.
  
  
  METHODS
  A standard model for corneal LC recruitment, application of cautery to the central corneal surface was used, and the differential gene expression levels of a panel of chemokines and chemokine receptors were determined by RNase protection assay. Chemokine receptor-knockout mice were used to evaluate the recruitment of MHC class II(+) LCs to the corneal epithelium. To determine the sensitivity of selected chemokines to IL-1 and TNF-alpha stimulation, the chemokine gene expression pattern was analyzed after blockade of IL-1 and TNF receptors.
  
  
  RESULTS
  CCR1, -2, and -5 were overexpressed in corneas after cauterization. Topical administration of soluble TNF receptor I and IL-1 receptor antagonist, which abrogated corneal LC recruitment, significantly suppressed the gene transcription levels of the ligands of CCR1 and/or -5, regulated on activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta. The recruitment of major histocompatibility complex (MHC) class II(+) LC was significantly suppressed in CCR5(-/-) mice and blockade of RANTES and MIP-1beta, but not in CCR1(-/-), CCR2(-/-)/MIP-1alpha(-/-), or MIP-1alpha(-/-) mice. The evaluation of epithelial CD11c(+) LC cells by confocal microscopy revealed coexpression for CCR5 primarily among B7(-) (CD80(-)/CD86(-)) subsets of these LCs but not among the mature B7(+) subsets of CD11c(+) LCs.
  
  
  CONCLUSIONS
  These data suggest that CCR5 plays a critical role in mediating recruitment and mobilization of MHC class II(+) LCs into the corneal epithelium. Targeting CCR5 and its ligands may be a new strategy for modulating immunity.
authors.affiliation: Laboratory of Immunology, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA. syamagami-tky@umin.ac.jp
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamagami
authors.forename: Pedram
authors.initials: P
authors.lastname: Hamrah
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Dai
authors.initials: D
authors.lastname: Miyazaki
authors.forename: Iva
authors.initials: I
authors.lastname: Dekaris
authors.forename: Tracey
authors.initials: T
authors.lastname: Dawson
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: M Reza
authors.initials: MR
authors.lastname: Dana
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D019573:Epithelium, Corneal / Q000502:physiology*; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D007801:Langerhans Cells / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D000949:Histocompatibility Antigens Class II; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha