Elucidating the role of neuregulin-1 in glial and immune response following traumatic spinal cord injury
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Spinal cord injury (SCI) elicits a robust glial and neuroinflammatory response that governs secondary injury processes and causes progressive neural degeneration and loss of neurological function. Activated glial and immune cells produce a plethora of inhibitory and toxic mediators that lay the foundation for a non-permissive microenvironment for neural repair and regeneration. Resident astrocytes and microglia together with blood-borne monocytes, T cells and B cells are the main orchestrators of secondary injury processes following SCI. Despite detrimental effects, these cells possess the ability to play pro-regenerative roles in response to proper modulatory signals from their microenvironment. Hence, identifying new therapeutic targets to promote the supportive aspect of glial and immune response is a viable approach for the treatment of SCI. To develop such targeted therapies, it is necessary to understand the endogenous mechanisms that regulate astrogliosis and neuroinflammation following SCI. Our team has previously discovered an acute and sustained depletion in spinal cord tissue levels of the neuronally derived Neuregulin-1 (Nrg-1) following SCI. Further studies by our group established a correlation between the injury-induced depletion of Nrg-1 and the inadequate oligodendrocyte replacement after SCI. Similar to oligodendrocytes, glial and immune cells also express Nrg-1 receptors, ErbB2, 3, 4, suggesting potential ramifications of Nrg-1 dysregulation on glial activity and neuroinflammation. Recent studies have also identified an immunomodulatory role for Nrg-1 in ischemic brain injuries. Based on this body of evidence, we hypothesized that diminished tissue levels of Nrg-1 in the injured spinal cord contribute to the imbalanced glial and immune response following SCI. Using an in vitro model of activated astrocytes and microglia and a clinically relevant in vivo model of rat compressive-contusive SCI, we unravel the role of Nrg-1 in regulating II astrogliosis and immune response following SCI. We show for the first time that Nrg-1 treatment moderates several detrimental characteristic aspects of activated glia such as chondroitin sulfate proteoglycans (CSPGs), nitric oxide (NO) and pro-inflammatory cytokine production. Mechanistically, we demonstrate that Nrg-1 effects on activated glia are mediated through an ErbB2/3 heterodimer complex and activation of Erk1/2 and STAT3 pathways. In SCI, our comprehensive analysis of immune and glial response using Western blotting, qPCR, immunohistochemistry and flow cytometry shows that Nrg-1 treatment reduces glial scar formation and induces a pro-regenerative regulatory phenotype in T and B cells and macrophages in the spinal cord and peripheral blood during the acute and chronic stages of SCI. Nrg-1 fosters a more balanced post-SCI microenvironment by attenuating antibody deposition and expression of pro-inflammatory cytokines and chemokines such as IL-6, IL-1β and TNF-⍺ while upregulating pro-regenerative mediators such as arginase-1, CCL11 and IL-10. Moreover, Nrg-1 bio- availability significantly improves neural tissue preservation and recovery of neurological function following SCI. Our work provides novel insights to into the role and mechanisms of Nrg-1 modulation of glial activation and neuroinflammation in SCI. It also establishes the promise of Nrg-1 treatment as a candidate immunotherapy for traumatic SCI and other CNS neuroinflammatory conditions.