title: Differential effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated immune reactions on murine P0106-125 -induced experimental autoimmune neuritis.
abstract: OBJECTIVE
  The role of chemokines and their receptors, which regulate trafficking and homing of leucocytes to inflamed organs in human or murine autoimmune neuritis, has not yet been elucidated in detail, Therefore, the role of the chemokine receptors CXCR4 and CXCR7 and their ligand CXCL12 was studied in autoimmune-mediated inflammation of the peripheral nervous system.
  
  
  METHODS
  CXCL12/CXCR4 and/or CXCL12/CXCR7 interactions were specifically inhibited by the compounds AMD3100 or CCX771, respectively, in experimental autoimmune neuritis (EAN) of C57BL/6J mice immunized with P0106-125 peptide.
  
  
  RESULTS
  Disease activity was significantly suppressed by blocking CXCR7 while antagonization of CXCR4 enhanced disease activity. Enhanced disease activity was accompanied by significantly increased transcription of IFN-γ, IL-12 and TNF-α mRNA in regional lymph nodes and spleen as well as by increased serum levels of IFN-γ. Furthermore, by blocking CXCR4, expression of the cell adhesion molecules ICAM-1 and VCAM-1 was upregulated on vascular endothelial cells of the sciatic nerve, which coincided with significantly increased infiltration of the sciatic nerve by CD4+ T cells and macrophages. Remarkably, combined antagonization of both CXCR4 and CXCR7 significantly suppressed disease activity. This was accompanied by increased frequencies of activated and highly IFN-γ-expressing, P0106-125 -specific T cells in regional lymph nodes and spleen; however, these cells were unable to infiltrate the sciatic nerve.
  
  
  CONCLUSIONS
  These data suggest differential and hierarchically ordered roles for CXCR4/CXCL12- vs. CXCR7/CXCL12-dependent effects during EAN: CXCR7/CXCL12 interaction is a gatekeeper for pathogenic cells, regardless of their CXCR4/CXCL12-dependent state of activation.
authors: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors: A
authors: A
authors: Brunn
authors: O
authors: O
authors: Utermöhlen
authors: M
authors: M
authors: Mihelcic
authors: M
authors: M
authors: Sánchez-Ruiz
authors: M
authors: M
authors: Carstov
authors: T
authors: T
authors: Blau
authors: I
authors: I
authors: Ustinova
authors: M
authors: M
authors: Penfold
authors: M
authors: M
authors: Montesinos-Rongen
authors: M
authors: M
authors: Deckert
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009444:Neuritis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D054387:Receptors, CXCR / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D011412:Propanolamines; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1; C056748:P 0160
keywords: CXCL12; CXCR4; CXCR7; chemokines; cytokines; murine EAN