Abstract
BackgroundSpinal cord injury (SCI) triggers a robust neuroinflammatory response that governs secondary injury mechanisms with both degenerative and pro-regenerative effects. Identifying new immunomodulatory therapies to promote the supportive aspect of immune response is critically needed for the treatment of SCI. We previously demonstrated that SCI results in acute and permanent depletion of the neuronally derived Neuregulin-1 (Nrg-1) in the spinal cord. Increasing the dysregulated level of Nrg-1 through acute intrathecal Nrg-1 treatment enhanced endogenous cell replacement and promoted white matter preservation and functional recovery in rat SCI. Moreover, we identified a neuroprotective role for Nrg-1 in moderating the activity of resident astrocytes and microglia following injury. To date, the impact of Nrg-1 on immune response in SCI has not yet been investigated. In this study, we elucidated the effect of systemic Nrg-1 therapy on the recruitment and function of macrophages, T cells, and B cells, three major leukocyte populations involved in neuroinflammatory processes following SCI.MethodsWe utilized a clinically relevant model of moderately severe compressive SCI in female Sprague-Dawley rats. Nrg-1 (2 μg/day) or saline was delivered subcutaneously through osmotic mini-pumps starting 30 min after SCI. We conducted flow cytometry, quantitative real-time PCR, and immunohistochemistry at acute, subacute, and chronic stages of SCI to investigate the effects of Nrg-1 treatment on systemic and spinal cord immune response as well as cytokine, chemokine, and antibody production.ResultsWe provide novel evidence that Nrg-1 promotes a pro-regenerative immune response after SCI. Bioavailability of Nrg-1 stimulated a regulatory phenotype in T and B cells and augmented the population of M2 macrophages in the spinal cord and blood during the acute and chronic stages of SCI. Importantly, Nrg-1 fostered a more balanced microenvironment in the injured spinal cord by attenuating antibody deposition and expression of pro-inflammatory cytokines and chemokines while upregulating pro-regenerative mediators.ConclusionWe provide the first evidence of a significant regulatory role for Nrg-1 in neuroinflammation after SCI. Importantly, the present study establishes the promise of systemic Nrg-1 treatment as a candidate immunotherapy for traumatic SCI and other CNS neuroinflammatory conditions.
Highlights
Spinal cord injury (SCI) triggers a robust neuroinflammatory response that governs secondary injury mechanisms with both degenerative and pro-regenerative effects
We demonstrate that systemic bioavailability of Nrg-1 induces a pro-regenerative immune response in leukocytes that fosters a supportive environment for repair and regeneration in the injured spinal cord
Flow cytometric verification of antibody specificity on injured and uninjured spinal cord tissue. (A–C) Spinal cord immune cells were gated for the detection of macrophages and their pro-inflammatory (M1, CD45+CD68+CD86+) and pro-regenerative (M2, CD45+CD68+CD163+) subpopulations
Summary
Spinal cord injury (SCI) triggers a robust neuroinflammatory response that governs secondary injury mechanisms with both degenerative and pro-regenerative effects. Activated T cells stimulate B cells, through a host of cytokines and signaling molecules, to produce autoreactive antibodies against spinal cord tissue [6] causing tissue damage through antibody-mediated cytotoxicity [7, 8] These processes collectively lead to an imbalanced and dysregulated milieu that impedes repair and regeneration after SCI [1]. Given the profound impact of neuroinflammation on SCI pathophysiology, it is critical to unravel endogenous mechanisms that regulate immune cells after injury. This knowledge is vital for developing immunotherapies that can harness the potential of immune cells in fostering a supportive microenvironment for spinal cord repair and regeneration
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