title: Pathogenesis of herpetic stromal keratitis in CCR5- and/or CXCR3-deficient mice.
abstract: OBJECTIVE
  Herpetic stromal keratitis (HSK) is an immunopathological reaction to herpes simplex virus type 1 (HSV-1) corneal infection. It has been reported that CD4+ cells play the most important role in the pathogenesis of this disease. In this study, we have focused on two chemokine receptors, CCR5 and CXCR3, which are expressed on CD4+ Th1 cells in mice HSK model.
  
  
  METHODS
  CCR5-deficient (CCR5KO), CXCR3-deficient (CXCR3KO), CCR5/CXCR3 double-deficient (DKO), and wild type (WT) mice (C57/BL6 background) were infected intracorneally with HSV-1 (CHR3 strain). The corneas were examined biomicroscopically, and cryosections of the corneas were examined histologically and immunohistochemically. Real-time RT-PCR and RNase protection assay (RPA) were performed, and the virus titers were measured in excised eyes and trigeminal ganglia (TG).
  
  
  RESULTS
  The HSK clinical severity in DKO mice was significantly lower than that in WT mice, and this was reversed by transfer of cells from the spleen of WT mice to DKO mice. Histologically, the numbers of T cells (CD4+ and CD8+ cells) and neutrophils infiltrating the cornea were significantly fewer in CCR5KO, CXCR3KO, and DKO mice. Transcript levels of immune-related cell surface marker in the eye by RPA were reduced in DKO mice. The expression of I-TAC was significantly increased in the cornea of CCR5KO mice, and MIP-1alpha and MIP-1beta were significantly lower in CXCR3KO mice than in WT mice by RT-PCR. There were no significant differences of virus titers in the eye and TG among any groups of mice except the increase in the TG of DKO mice on day 5 PI.
  
  
  CONCLUSIONS
  The suppression of chemotaxis and activation of CD4+ Th1 cells by the lacking of CXCR3 and CCR5 causes a decrease of other infiltrating cells, resulting in a lower severity of HSK. These results suggest that targeting chemokine receptors is a promising way to treat HSK.
authors.affiliation: Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Tottori, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Komatsu
authors.forename: Dai
authors.initials: D
authors.lastname: Miyazaki
authors.forename: Kei
authors.initials: K
authors.lastname: Morohoshi
authors.forename: Chuan-Hui
authors.initials: CH
authors.lastname: Kuo
authors.forename: Akiko
authors.initials: A
authors.lastname: Kakimaru-Hasegawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Komatsu
authors.forename: Sachiko
authors.initials: S
authors.lastname: Namba
authors.forename: Makoto
authors.initials: M
authors.lastname: Haino
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D003319:Corneal Stroma / Q000294:innervation / Q000378:metabolism / Q000821:virology*; D004279:DNA, Viral / Q000235:genetics; D018628:Gene Dosage; D018259:Herpesvirus 1, Human / Q000502:physiology; D007124:Immunoenzyme Techniques; D016849:Keratitis, Herpetic / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000502:physiology; D054367:Receptors, CXCR3 / Q000172:deficiency* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012668:Trigeminal Ganglion / Q000821:virology; D014709:Vero Cells / Q000821:virology
chemical_list: C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054371:Chemokine CXCL11; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D004279:DNA, Viral; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054367:Receptors, CXCR3