The Chemokine Fractalkine Inhibits Fas-Mediated Cell Death of Brain Microglia

Abstract

Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.

Chemokine Receptor CX3CR1 Mediates Skin Wound Healing by Promoting Macrophage and Fibroblast Accumulation and Function

“…How CX3CR1 works in the model requires further definition: does it only promote monocyte/macrophage influx from the blood into the wound as the transfer experiments suggest, or does it also mediate macrophage retention in the wound? CX3CL1-CX3CR1 signaling has also been reported to maintain cell survival and inhibit Fas-dependent cell death of brain microglia in vitro (47). Perhaps it also regulates survival of dermal macrophages in wounded skin.…”

CX3CL1 Up-Regulation Is Associated with Recruitment of CX3CR1+ Mononuclear Phagocytes and T Lymphocytes in the Lungs during Cigarette Smoke-Induced Emphysema

“…Others have previously reported that CX3CL1 provides cell-survival signals on ligation of CX3CR1 50,51 and inhibits Fas-mediated apoptosis in microglial cells. 52 Whether or not the CX3CL1-CX3CR1 pathway promotes cell-survival signals and contributes to the accumulation of alveolar and parenchymal macrophages observed in COPD is not known.…”

Identification of Novel Wilms' Tumor Suppressor Gene Target Genes Implicated in Kidney Development

“…In this regard, WT1-induced growth factors which we have identified, such as CX3CL1, IL-11, and FGF-1, may confer mesenchymal cell survival and differentiation through autocrine circuits. CX3CL1/Fractalkine inhibits apoptosis in neurons and microglia (53,54), and IL-11 protects skin from UVB-induced apoptosis (55) and from nephrotoxic serum-induced glomerulonephritis (56). The importance of FGF signaling in kidneys has been demonstrated using a transgenic mouse expressing dominant negative FGF receptor (57).…”