Macrophage Migration Inhibitory Factor Promotes Chemotaxis of Astrocytes through Regulation of Cholesterol 25-Hydroxylase Following Rat Spinal Cord Injury

Oxysterol derived from cholesterol metabolism is involved in the inflammatory activation, and consequently in development of major chronic diseases. Multiple cytokines have been found to induce the expression of cholesterol metabolism-related enzymes. Several studies have shown that the protein level of cholesterol-25-hydroxylase (CH25H) is remarkably increased in response to injury of central nervous system (CNS), but little is known about the mechanisms of cytokine-induced expression of CH25H in specific cell types, and the resultant effects. In the present study, we demonstrated that ch25h expression was significantly upregulated in the astrocytes of rat injured spinal cord, in parallel with those of MIF. Administration of MIF inhibitor 4-IPP in the lesion sites attenuated injury-induced ch25h expression. MIF facilitated ch25h expression of astrocytes through interaction with CD74 membrane receptor, which in turn promoted production of chemokines, as identified by transcriptome profiles. MIF-induced release of oxysterol 25-hydroxycholesterol (25-HC) from astrocytes affects cell migration, but inhibited cell viability in dose-dependent manner, suggesting that MIF aggravates progressive neuropathology through regulation of cholesterol metabolism following CNS injury. These results have provided a novel mechanism and a potential therapeutic strategy for injured CNS.