CLONING OF RAT HIV-1-CHEMOKINE CORECEPTOR CKR5 FROM MICROGLIA AND UP-REGULATION OF ITS MESSENGER-RNA IN ISCHEMIC AND ENDOTOXINEMIC RAT-BRAIN

Chemokine receptors play a crucial role in the recruitment of immune c ells to sites of inflammation. Although chronic diseases of the brain are often accompanied by inflammatory events, there is presently no in formation about the occurrence and regulation of these receptors in th e central nervous system (CNS), Moreover, one CC-chemokine receptor, C KR5, has recently been identified as coreceptor for HIV-1 entry into m acrophages, HIV-1 target cells in brain are macrophage-related microgl ia, which suggests that they are infected by the same mechanism (He et al,,: Nature 385:645-649, 1997), Although rats are not susceptible to HIV-1 infection, they can be used to study chemokine receptor regulat ion in a variety of brain pathologies. After cloning CC-CKR5 and estab lishing reverse transcriptase polymerase chain reaction (RT-PCR) for i ts ligands macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and regulated on activation, normal T cell-expressed and secreted (RAN TES), we studied expression of these four mRNAs in purified microglia and compared it with their expression in rat brain, Lipopolysaccharide (LPS)-treated microglia showed transiently increased mRNA levels of b oth CKR5 and its ligands, Similar data were obtained from brains of LP S-injected rats, In middle cerebral artery occluded (MCAO)-animals, RA NTES mRNA was unaffected, whereas CKR5 mRNA showed a sustained rise un til 96 hr after surgery, MIPs exogenously added to microglial cultures markedly reduced CKR5 mRNA expression, whereas RANTES did not, MIP mR NAs, in contrast to RANTES and CKR5 mRNAs, were undetectable in normal brain, RANTES appears to play a role distinct from MIPs in brain, In summary, upregulation of CC-chemokines and CKR5 in the CNS upon bacter ial infection or in ischemia may impact on microglial activation stage and result in increased risk of HIV-1 infection, J, Neurosci, Res. 53 :16-28, 1998 (C) 1998 Wiley Liss, Inc.