The tyrosine kinase receptor RON and its ligand, macrophage stimulating protein 
(MSP), exert inhibitory effects on systemic innate immunity, but their CNS 
expression and impact on human neuroinflammatory diseases are unknown were RON 
and MSP present in human brain perivascular macrophages and microglia, but RON 
mRNA and protein abundance in the CNS were diminished in both MS patients and 
the MS animal model, experimental autoimmune encephalomyelitis (EAE). Treatment 
of differentiated human monocytoid cells with MSP resulted in significant 
reduction of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and MMP-9 
mRNA levels, whereas minimal effects were observed in human astrocytes. After 
induction of EAE, RON knockout and heterozygote animals exhibited significantly 
increased CNS proinflammatory gene (TNF-alpha, MMP-12) expression compared with 
wild-type littermate controls, although IL-4 levels were suppressed in both 
RON-deficient groups. Neurological disease in RON-deficient animals showed a 
more rapid onset with overall worsened severity, together with exacerbated 
demyelination, axonal injury, and neuroinflammation after EAE induction. The 
proto-oncogene, c-Cbl, which modulates ubiquitylation of RON, was increased in 
glia in both MS brains and EAE spinal cords. Thus, the MSP-RON pathway 
represents a novel regulatory mechanism within the CNS by which innate immunity 
and its pathogenic effects could be targeted for future therapeutic 
interventions.