THE DUFFY ANTIGEN RECEPTOR FOR CHEMOKINES - STRUCTURAL-ANALYSIS AND EXPRESSION IN THE BRAIN

The Duffy antigen receptor for chemokines (DARC) is expressed in human erythrocytes and on endothelial cells lining postcapillary venules in kidney and spleen, DARC is a promiscuous chemokine receptor and a bin ding protein for the malarial parasite Plasmodium vivax. The expressio n of DARC by subsets of endothelial cells and neurons in discrete anat omic sites in the brain suggests that this enigmatic receptor may have multiple roles in normal and pathological physiology, Conservation of this promiscuous chemokine binding function is evident from the simil arity in nucleotide sequence of DARC homologues from multiple species, as well as the hgh-affinity binding of human chemokines to murine and avian erythrocytes, Analysis of the functional domains of DARC using chimeric receptors and monoclonal antibodies to multiple extracellular domains localized chemokine binding to structures in the amino termin al extracellular domain (E1). Scatchard analysis demonstrated that a c himeric DARC receptor, composed of the E1 domain of DARC and the predi cted hydrophobic helices and loops of interleukin-8RB (IL-8RB), bound IL-8, and MGSA with K-D values almost identical to the wild type recep tors and bound a repertoire of C-X-C and C-C chemokines characteristic of DARC, Although numerous reports have demonstrated that chemokines such as IL-8 are expressed in the brain, presumably by glial cells, li ttle insight into the nature of their role in normal or pathological p hysiology in the nervous system has developed because the target cells that express the corresponding receptors have not yet been identified , Northern blotting experiments suggest that mRNA encoding DARC are ex pressed in the central nervous system, however, interpretation of this is unclear because of the ubiquitous expression of DARC Lining postca pillary venules, This study provides direct evidence to localize expre ssion of DARC in the cental nervous system, Immunohistochemical examin ation of human archival sections of the brain with monoclonal antibodi es specific for DARC localize expression of DARC to cell bodies and pr ocesses of Purkinjie cells in the cerebellum, The immunohistochemical findings were supported by analysis of chemokine binding and radioliga nd crosslinking with membranes made from various brain fractions, The hierarchical expression of DARC in neurons in the cerebellum suggests that chemokines may play an important role in the modulation of neuron al activity by glial cells.