Neuregulin-1 elicits a regulatory immune response following traumatic spinal cord injury
Bibliographic record
Abstract
BACKGROUND: Spinal 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: We 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".