期刊
GLIA
卷 65, 期 7, 页码 1152-1175出版社
WILEY
DOI: 10.1002/glia.23150
关键词
functional recovery; glial scar; IL-10; neuroinflammation; neuregulin-1; spinal cord injury
资金
- Canadian Institutes of Health Research (CIHR) [MOP 133721]
- Canadian Paraplegic Association of Manitoba
- Manitoba Paraplegic Foundation
- CHRIM
- Research Manitoba
- Rick Hansen Institute
- U of M
- CIHR
- American Association of Neurology (AAN)
Spinal cord injury (SCI) results in glial activation and neuroinflammation, which play pivotal roles in the secondary injury mechanisms with both pro- and antiregeneration effects. Presently, little is known about the endogenous molecular mechanisms that regulate glial functions in the injured spinal cord. We previously reported that the expression of neuregulin-1 (Nrg-1) is acutely and chronically declined following traumatic SCI. Here, we investigated the potential ramifications of Nrg-1 dysregulation on glial and immune cell reactivity following SCI. Using complementary in vitro approaches and a clinically-relevant model of severe compressive SCI in rats, we demonstrate that immediate delivery of Nrg-1 (500 ng/day) after injury enhances a neuroprotective phenotype in inflammatory cells associated with increased interleukin-10 and arginase-1 expression. We also found a decrease in proinflammatory factors including IL-1 beta, TNF-alpha, matrix metalloproteinases (MMP-2 and 9) and nitric oxide after injury. In addition, Nrg-1 modulates astrogliosis and scar formation by reducing inhibitory chondroitin sulfate proteoglycans after SCI. Mechanistically, Nrg-1 effects on activated glia are mediated through ErbB2 tyrosine phosphorylation in an ErbB2/3 heterodimer complex. Furthermore, Nrg-1 exerts its effects through downregulation of MyD88, a downstream adaptor of Toll-like receptors, and increased phosphorylation of Erk1/2 and STAT3. Nrg-1 treatment with the therapeutic dosage of 1.5 mu g/day significantly improves tissue preservation and functional recovery following SCI. Our findings for the first time provide novel insights into the role and mechanisms of Nrg-1 in acute SCI and suggest a positive immunomodulatory role for Nrg-1 that can harness the beneficial properties of activated glia and inflammatory cells in recovery following SCI.
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