Midkine and multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune neurological disease characterized by inflammatory demyelination with subsequent neuronal damage in the CNS. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thought as autoreactive Th1 and Th17 cell-mediated diseases. CD4(+) CD25(+) FoxP3(+) regulatory T-cell (Treg) plays a pivotal role in autoimmune tolerance, and tolerogenic dendritic cells (DCreg) drive the development of inducible Treg cells. Thus, a dysfunction in the development of Treg and DCreg leads to the development of autoimmune diseases. However, the factors that regulate Treg and DCreg are largely unknown. We recently showed that removal of midkine (MK) suppressed EAE due to an expansion of the Treg cell population as well as a decrease in the numbers of autoreactive Th1 and Th17 cells. MK decreased the Treg cell population by suppressing the phosphorylation of STAT5, which is essential for the expression of Foxp3, the master transcriptional factor of Treg cell differentiation. Furthermore, MK reduces the DCreg cell population by inhibiting the phosphorylation of STAT3, which is critical for DCreg development. Blockade of MK signalling by a specific RNA aptamer significantly elevated the population of DCreg and Treg cells and ameliorated EAE without detectable adverse effects. Therefore, the inhibition of MK may provide an effective therapeutic strategy against autoimmune diseases including MS.


BACKGROUND
This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan.
Hideyuki
H
Takeuchi
D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D000078792:Midkine; D009103:Multiple Sclerosis / Q000276:immunology*
D052157:Aptamers, Nucleotide; D016207:Cytokines; D000078792:Midkine
aptamer; experimental autoimmune encephalomyelitis; midkine; multiple sclerosis; regulatory T-cell; tolerogenic dendritic cell