gms | German Medical Science

Objective: Chemokines and their receptors are implicated in signaling of homeostatic and inflammatory processes in the brain. The transmembrane chemokine CXCL16 is expressed in brain endothelial and reactive astroglial cells and shed to a soluble form whereas its receptor CXCR6 is expressed by immortalized early glial progenitor cells and less abundant by astrocytes and microglia.

Results: Here, we describe the function of CXCL16 and its receptor CXCR6/Bonzo in murine glial cells. As shown by quantitative RT-PCR, CXCR6 expression increases during development, with no detectable expression at embryonic state, reaching a peak at postnatal day 6 and decreasing afterwards to low level in adult brain. CXCR6 is also highly expressed in glial precursor cells differentiated from neural stem cells as well as in a glial precursor cell line (GPC) which we define by high expression of Nestin and A2B5 and low expression of glial fibrillary acidic protein. Stimulation of these GPCs by soluble CXCL16 induces the PI3-kinase / Akt pathway resulting in the activation of the transcription factor AP-1, but not of NFκB. As biological responses, soluble CXCL16 upregulates its own receptor and increases GPC proliferation; this can be inhibited by the PI3-kinase inhibitor Wortmannin. CXCL16 stimulates cell migration in wound-healing and in spheroid confrontation assays. GPC invasion into CXCL16-expressing spheroids can be blocked by sheddase inhibitors and CXCL16-antibodies.

Conclusions: Thus, CXCL16 recruits CXCR6-positive glial precursor cells, enhances their invasion and proliferation. This mechanism could be responsible, at least in part, for the attraction of glial precursor cells and subsequent astrogliosis to sites of inflammation, neurodegeneration, ischemia and malignant transformation in the brain where CXCL16 is induced by cytokines.