Differential effects of CXCR4‐CXCL12‐ and CXCR7‐CXCL12‐mediated immune reactions on murine P0_106–125‐induced experimental autoimmune neuritis

Abstract

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 CXCR 4 and CXCR 7 and their ligand CXCL 12 was studied in autoimmune‐mediated inflammation of the peripheral nervous system. Methods CXCL 12/ CXCR 4 and/or CXCL 12/ CXCR 7 interactions were specifically inhibited by the compounds AMD 3100 or CCX 771, respectively, in experimental autoimmune neuritis ( EAN ) of C 57 BL /6 J mice immunized with P 0 106–125 peptide. Results Disease activity was significantly suppressed by blocking CXCR 7 while antagonization of CXCR 4 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 CXCR 4, 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 CD 4+ T cells and macrophages. Remarkably, combined antagonization of both CXCR 4 and CXCR 7 significantly suppressed disease activity. This was accompanied by increased frequencies of activated and highly IFN ‐γ‐expressing, P 0 106–125 ‐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 CXCR 4/ CXCL 12‐ vs. CXCR 7/ CXCL 12‐dependent effects during EAN : CXCR 7/ CXCL 12 interaction is a gatekeeper for pathogenic cells, regardless of their CXCR 4/ CXCL 12‐dependent state of activation.