Our studies use experimental autoimmune encephalomyelitis (EAE) as a model to investigate pathological events related to Multiple Sclerosis. The primary focus is to determine the contribution of the fractalkine receptor (CX3CR1) to disease severity. Fractalkine (CX3CL1) and its receptor CX3CR1 provide a physiologically-relevant neuron-microglia communication mechanism. Fractalkine is a unique central nervous system (CNS) chemokine present on neuronal membranes and capable of being released as a soluble protein by constitutive or stress-activated ADAM-family protease activity. Fractalkine exerts its functions by binding to CX3CR1 on microglial cells. Although they are mainly produced in the CNS, Fractalkine and CX3CR1 also have a distinctive peripheral pattern of expression. Fractalkine is found at low levels in endothelial and some epithelial cells of selected tissues such as kidney, lung, prostate and heart, but not spleen or liver. CNS endothelial cells do not express fractalkine. Circulating monocytes, dendritic cells and NK cells express CX3CR1. In vitro studies suggested that soluble fractalkine mediates microglial chemoattraction but, surprisingly inhibits microglial activation, and protects microglia from apoptosis.
We intend to clarify the role of fractalkine/CX3CR1 in the brain, research that is instrumental for potential development of therapeutic agents. Some of the questions we are addressing include:
- Does CX3CR1 play a role in the trafficking of microglial precursors?
- Does CX3CR1-deficiency on microglia or peripheral cells enhance neuronal/axonal pathology?
- How does CX3CR1-deficiency alter CNS immune responses?