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Aim 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 C57 BL/6 J 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. Conclusion 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. [ABSTRACT FROM AUTHOR]