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RON‐regulated innate immunity is protective in an animal model of multiple sclerosis
Author(s) -
Tsutsui Shigeki,
Noorbakhsh Farshid,
Sullivan Andrea,
Henderson Andrew J.,
Warren Kenneth,
ToneyEarley Kenya,
Waltz Susan E.,
Power Christopher
Publication year - 2005
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20502
Subject(s) - innate immune system , proinflammatory cytokine , neuroinflammation , immunology , microglia , tumor necrosis factor alpha , multiple sclerosis , experimental autoimmune encephalomyelitis , biology , inflammation , medicine , immune system
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)–1β, tumor necrosis factor (TNF)–α 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‐α, 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. Ann Neurol 2005;57:883–895