#2 Neuregulin-1 attenuates glial scarring and neuroinflammation and improves neurological recovery following traumatic spinal cord injury
Arsalan Alizadeh, University of Manitoba Graduate Studies; Hardeep Kataria, University of Manitoba Graduate Studies; Kallivalappil Thomas Santhosh, University of Manitoba Graduate Studies; Hesam Movassagh, University of Manitoba Graduate Studies; Abdelilah Soussi Gounni, University of Manitoba Graduate Studies; Soheila Karimi-Abdolrezaee, University of Manitoba Graduate Studies
Astrogliosis and neuroinflammation play pivotal pro- and anti-regenerative roles in the secondary injury mechanisms after spinal cord injury (SCI). We previously reported for the first time that expression of Neuregulin-1 (Nrg-1) is dramatically and permanently downregulated in acute SCI. Glial and immune cells express Nrg-1 receptors, ErbB2, 3, 4, suggesting the potential ramifications of Nrg-1 dysregulation on glial activity and neuroinflammation. In this study, we sought to unravel the role of Nrg-1 in regulating astrogliosis and immune response following SCI.
In vitro, we used primary mixed culture of rat astrocytes and microglia activated by lipopolysaccharide (LPS). In vivo, we employed a rat model of compressive SCI. We delivered recombinant human Neuregulin-1 (rhNrg-1β1) intrathecally for up to 6 weeks. We conducted flow cytometry, Western blotting, immunoprecipitation, gelatin zymography and stereology-based immunohistology at 3, 7, 14, 42 and 70 days post-SCI. SCI rats were assessed for their locomotion and sensory recovery weekly.
We show that Nrg-1 treatment attenuates the expression “chondroitin sulphate proteoglycans” (CSPGs) and GFAP, two major components of the glial scar. Nrg-1 treatment fosters a pro-regenerative regulatory phenotype in infiltrated T and B cells and increases IL-10 expression that leads to a global decrease in pro-degenerative markers such as IL-1β, TNF-α and matrix metalloproteinases (MMP-2 and 9) after SCI. Mechanistically, we demonstrate that Nrg-1 effects on activated glia are mediated through ErbB2/3 heterodimer complex. Intracellularly, Nrg-1 exerts its effects through downregulation of Myd88, a downstream adaptor of Toll-like receptors, and phosphorylation of Erk1/2 and STAT3. Importantly, Nrg-1 treatment significantly improves functional recovery following SCI.
Our findings for the first time provide novel insight into the promising role of Nrg-1 in modulating activated glial and immune cells for repair and recovery following SCI. Supported by the CIHR, CPA and RM.