CXCR4 and CXCR7 form a functional receptor unit for SDF‐1/CXCL12 in primary rodent microglia

Abstract

Aims Microglial cells have been originally identified as a target for the CXC chemokine, SDF ‐1, by their expression of CXCR 4. More recently, it has been recognized that SDF ‐1 additionally binds to CXCR 7, which depending on the cell type acts as either a nonclassical, a classical or a scavenger chemokine receptor. Here, we asked whether primary microglial cells additionally express CXCR 7 and if so how this chemokine receptor functions in this cell type. Methods CXCR 4 and CXCR 7 expression was analysed in cultured rat microglia and in the brain of animals with permanent occlusion of the middle cerebral artery ( MCAO ) by either W estern blotting, RT ‐ PCR , flow cytometry and/or immunocytochemistry. The function of CXCR 4 and CXCR 7 was assessed in the presence of selective antagonists. Results Cultured primary rat microglia expressed CXCR 4 and CXCR 7 to similar levels. Treatment with SDF ‐1 resulted in the activation of Erk 1/2 and Akt signalling. Erk 1/2 and Akt signalling were required for subsequent SDF ‐1‐dependent promotion of microglial proliferation. In contrast, Erk 1/2 signalling was sufficient for SDF ‐1‐induced migration of microglial cells. Both SDF ‐1‐dependent signalling and the resulting effects on microglial proliferation and migration were abrogated following pharmacological inactivation of either CXCR 4 or CXCR 7. Moreover, treatment of cultured microglia with lipopolysaccharide resulted in the co‐ordinated up‐regulation of CXCR 4 and CXCR 7 expression. Likewise, reactive microglia accumulating in the area adjacent to the lesion core in MCAO rats expressed both CXCR 4 and CXCR 7. Conclusions CXCR 4 and CXCR 7 form a functional receptor unit in microglial cells, which is up‐regulated during activation of microglia both in vitro and in vivo .