IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.