Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice.

ABSTRACT

Glia maturation factor (GMF), a primarily CNS localized protein was discovered and characterized in our laboratory. We previously demonstrated that GMF is the upstream regulator for excessive production and release of proinflammatory cytokines/chemokines in brain cells leading to the destruction of oligodendrocytes, the myelin forming cells, and neurons. We also reported that mice lacking endogenous GMF (GMF-deficient, GMF-KO) were resistant to myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)) induced EAE, since immunization induced only delayed EAE with diminished severity. In the present study we show that a replication-defective adenovirus-GMF construct caused expression of GMF in CNS of GMF-KO mice and reinstated MOG(35-55) induced early and severe EAE. Our results show that MOG(35-55) immunization caused only a muted EAE and inflammation/demyelination in mice lacking endogenous GMF. The diminished incidence of EAE in GMF-KO mice was consistent with the significantly reduced expressions of cytokines/chemokines. The muted severity of EAE in GMF-KO mice was restored to full blown levels upon reintroduction of GMF using an adeno-GMF-virus (Adv-GMF) vector. Consistent with the clinical findings, histological examination of the CNS of mice with EAE revealed profound differences between wild type (Wt), GMF-KO, and GMF-KO mice with re-introduced GMF (GMF-KO+Adv-GMF). Spinal cord sections from mice with EAE were analyzed for the infiltration of mononuclear cells (inflammation) and myelin loss (demyelination). In Wt mice, 40% of spinal cord quadrants were positive for demyelination and 45% of spinal cord quadrants were positive for inflammation at the peak of EAE. Drastically reduced infiltrates (15%) and demyelination (10%) were found in GMF-KO mice that developed reduced severity of EAE. Upon GMF reintroduction in GMF-KO mice, MOG(35-55) immunization caused extensive monocytes infiltration (48%) and demyelination (46%), similar to that observed in the immunized Wt mice. The levels of cytokine/chemokine in the spinal cords of mice at three time points, corresponding to the onset, peak severity and recovery period of EAE, show a distinct pattern of very large increases in IFN-γ, TNF-α, GM-CSF and MCP-1 in Wt and GMF-KO+Adv-GMF mice compared to GMF-KO and GMF-KO+Adv-LacZ mice.