The role of chemokines in the pathology of multiple sclerosis and other neuroinflammatory diseases

The recruitment of circulating leukocytes and resident glial cells to sites of CNS inflammation is dependent on the chemokine gradients they encounter and the chemokine receptors they express. Multiple sclerosis (MS), subacute sclerosing panencephalitis (SSPE) and coeliac disease (CD), with associated neurological complications, are neuroinflammatory diseases with different aetiologies, but which share common CNS neuropathological features including large perivascular inflammatory cell infiltrates, microglial hyperplasia and reactive astrocytosis. The results of this study suggest that in SSPE CNS the interferon -y-inducible a chemokines IP-10 and Mig, predominantly expressed by astrocytes and microglia, play a role in lesion formation. In contrast, the ßchemokine MEP-la, expressed both by perivascular macrophages and resident microglia, plays a role in the recruitment of inflammatory cells into CD cerebellar tissue. The highest levels of a- and ß-chemokine expression were detected in actively demyelinating MS lesions with high levels of inflammation and widespread demyelination. In these lesions, RANTES was predominantly expressed by the endothelium, MCP- l, IP-10 and Mig by reactive astrocytes, and MIP-lß by microglia. These findings suggest not all neuroinflammatory diseases with common pathological features share a common chemokine profile.

The highest level of chemokine receptor expression was also associated with chronic active MS lesions: infiltrating T-lymphocytes predominantly expressing CXCR3 and CCR5, and foamy macrophages within the lesion predominantly expressing CCR3, CCR5 and CCR8. In vitro studies confirmed the production of chemokines and the expression of chemokine receptors by isolated rat astrocytes and microglia following cytokine stimulation. The results of this study suggest chemokines play a critical role in the recruitment of cells to sites of inflammation in the CNS.