RON-regulated innate immunity is protective in an animal model of multiple sclerosis.
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.
Tsutsui
Shigeki
S
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Noorbakhsh
Farshid
F
Sullivan
Andrea
A
Henderson
Andrew J
AJ
Warren
Kenneth
K
Toney-Earley
Kenya
K
Waltz
Susan E
SE
Power
Christopher
C
D000818:Animals; D001369:Axons / Q000473:pathology; D002490:Central Nervous System / Q000276:immunology; D003711:Demyelinating Diseases / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D050722:Oncogene Protein v-cbl; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D012720:Severity of Illness Index; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C000715470:MAS1 protein, human; D050722:Oncogene Protein v-cbl; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C493849:Cbl protein, mouse