Abstract
Traumatic brain injury (TBI) commonly results in injury to the components of the white matter tracts, causing post-injury cognitive deficits. The myelin-producing oligodendrocytes (OLs) are vulnerable to TBI, although may potentially be replaced by proliferating oligodendrocyte progenitor cells (OPCs). The cytokine interleukin-1β (IL-1β) is a key mediator of the complex inflammatory response, and when neutralized in experimental TBI, behavioral outcome was improved. To evaluate the role of IL-1β on oligodendrocyte cell death and OPC proliferation, 116 adult male mice subjected to sham injury or the central fluid percussion injury (cFPI) model of traumatic axonal injury, were analyzed at two, seven, and 14 days post-injury. At 30 min post-injury, mice were randomly administered an IL-1β neutralizing or a control antibody. OPC proliferation (5-ethynyl 2′- deoxyuridine (EdU)/Olig2 co-labeling) and mature oligodendrocyte cell loss was evaluated in injured white matter tracts. Microglia/macrophages immunohistochemistry and ramification using Sholl analysis were also evaluated. Neutralizing IL-1β resulted in attenuated cell death, indicated by cleaved caspase-3 expression, and attenuated loss of mature OLs from two to seven days post-injury in brain-injured animals. IL-1β neutralization also attenuated the early, two day post-injury increase of microglia/macrophage immunoreactivity and altered their ramification. The proliferation of OPCs in brain-injured animals was not altered, however. Our data suggest that IL-1β is involved in the TBI-induced loss of OLs and early microglia/macrophage activation, although not the OPC proliferation. Attenuated oligodendrocyte cell loss may contribute to the improved behavioral outcome observed by IL-1β neutralization in this mouse model of diffuse TBI.
Highlights
Traumatic brain injury (TBI) is a complex disease induced by a broad spectrum of injury mechanisms that include a robust inflammatory response with both beneficial and deleterious effects on patient outcome.[1]
One sham-injured animal died in its home cage, and 15 central fluid percussion injury (cFPI) animals died at time of impact, resulting in a cFPI-related mortality rate of 13%
After seven and 14 dpi, no significant differences in Iba-1 immunoreactivity were observed between the experimental groups. These results show a subacute microglial/macrophage response after cFPI ameliorated by treatment using an IL-1b neutralizing antibody
Summary
Traumatic brain injury (TBI) is a complex disease induced by a broad spectrum of injury mechanisms that include a robust inflammatory response with both beneficial and deleterious effects on patient outcome.[1]. One key player is the pro-inflammatory cytokine interleukin-1b (IL-1b), increased after both experimental and human TBI.[19,20,21] IL1b is produced by activated microglia, astroglia, endothelial cells, and recruited leukocytes[22] and may have a dual role in OPC proliferation and myelin remodeling because it may be cytotoxic to mature OLs.[9,23,24] It can stimulate the production of growth factors known to induce the proliferation of OPCs. By using an antagonist to the IL-1 receptor, morphological and histological outcome was improved after experimental TBI.[23,25,26] In a series of experiments from our group, neutralization of IL-1b attenuated the inflammatory response, cerebral edema, and tissue loss and improved cognitive outcome in a focal TBI model in mice.[27,28] Recently, neutralization of IL-1b normalized the complex behavioral changes observed in a diffuse TBI model, the central fluid percussion model, in mice.[29] The mechanisms explaining the behavioral improvements observed by IL-1b neutralization have not been established. We hypothesized that neutralization of IL-1b may influence OL cell death, increase OPC proliferation, and attenuate microglial/macrophage activation after diffuse TBI in the mouse
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