#31 Neuregulin-1 augments remyelination and modulates inflammatory response following lysolecithin-induced demyelination in rat spinal
Hardeep Kataria, University of Manitoba; Arsalan Alizadeh, University of Manitoba; Ghazaleh M Shahriary, University of Manitoba; Shekoofeh Saboktakin Rizi, University of Manitoba; Ryan Henrie, University of Manitoba; Kallivalappil T Santhosh, University of Manitoba; James A Thliveris, University of Manitoba; Soheila Karimi-Abdolrezaee, University of Manitoba
Loss of oligodendrocytes and myelin damage are shared pathologies of central nervous system (CNS) injuries and demyelinating disorders across all age groups. Remyelination by endogenous precursor cells is hindered in the impermissible milieu of demyelinating lesions. Our recent evidence in spinal cord demyelinating lesions indicates that dysregulation of the growth factor Neuregulin-1 (Nrg-1) results in an imbalanced immune response that may underlie the limited endogenous myelin repair. Here, we explored the impact of Nrg-1 therapy on endogenous remyelination and neuroinflammation using in vivo and in vitro model systems.
Demyelination was induced by intraspinal lysolecithin (LPC) injections in adult female rats. Recombinant human Nrg-1β1 (rhNrg-1β1) was delivered intraspinally using biodegradable poly lactic-co-glycolic acid microcarriers for 3,7,14 and 21 days post-LPC injection. For in vitro studies, primary rat derived neural precursor cells (NPCs), dorsal root ganglion neurons and microglia were used. Spinal cord tissues and cell cultures were analyzed with ELISA, Western blotting, slot blotting, immunostaining, co-immunoprecipitation and electron microscopy.
We demonstrate that Nrg-1 protein levels are significantly reduced in LPC induced focal demyelinating lesions. Local rhNrg-1β1 treatment promoted generation and maturation of oligodendrocytes. Importantly, Nrg-1 therapy accelerated remyelination by both oligodendrocyte and Schwann cell populations leading to significant improvement in myelin thickness. Our in vitro assessments provide direct evidence that Nrg-1 treatment promotes oligodendrocytes myelination. Nrg-1 therapy remarkably reduced the expression of oligodendrocyte inhibitory factor Chondroitin sulfate proteoglycans and promoted a pro-regenerative inflammatory response by induction of interleukin-10 in demyelinating lesions. Nrg-1 significantly attenuated the production of pro-inflammatory cytokine interleukin-1β in activated microglia. Mechanistically, we show that Nrg-1 specifically mediates its effects through activation of ErbB2 and ErbB4 receptors.
In conclusion, our work uncovers a novel role for Nrg-1 in promoting a pro-regenerative microenvironment that fosters oligodendrocyte replacement and enhances remyelination process in demyelinating lesions of the CNS.