Absence of IL-1β positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury

Francesco Boato,Sofie Nelissen,Eva M Peters,Robert Nitsch,Sven Hendrix,Lies Geboes,Karen Rosenberger

doi:10.1186/1742-2094-10-6

Abstract

Precise crosstalk between the nervous and immune systems is important for neuroprotection and axon plasticity after injury. Recently, we demonstrated that IL-1β acts as a potent inducer of neurite outgrowth from organotypic brain slices in vitro, suggesting a potential function of IL-1β in axonal plasticity. Here, we have investigated the effects of IL-1β on axon plasticity during glial scar formation and on functional recovery in a mouse model of spinal cord compression injury (SCI). We used an IL-1β deficiency model (IL-1βKO mice) and administered recombinant IL-1β. In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1β. Consistently, the treatment significantly worsened the neurological outcome after SCI in mice compared with PBS controls. In contrast, the absence of IL-1β in IL-1βKO mice significantly improved recovery from SCI compared with wildtype mice. Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1βKO mice relative to controls. Our study for the first time characterizes the detrimental effects of IL-1β not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

Highlights

IL-1β is a 17 kDa protein and is one of the most extensively studied proinflammatory cytokines
To our knowledge this is the first study to investigate that the effect of recombinant IL-1β (rIL-1β)-mediated worsened neurological outcome after spinal cord compression injury (SCI) was due to a systemic effect of the cytokine, we applied 1 μg IL-1β systemically after lesion (Figure 3)
Quantification of Biotinylated dextran amine (BDA)-positive fibers, which were normalized to the total number of labeled corticospinal tract (CST) fibers cranial to the lesion center, showed that the percentage of fibers present 5 mm distal to the lesion was reduced about 15-fold in rIL-1β-treated mice compared with Phosphate-buffered saline (PBS)-treated mice (Figure 6A) and was increased about fivefold in IL1β deficiency (IL-1βKO) mice compared with WT (Figure 6B)

Summary

Introduction

IL-1β is a 17 kDa protein and is one of the most extensively studied proinflammatory cytokines. IL-1β is almost undetectable in the undamaged central nervous system (CNS), but its expression increases several fold after injury (including neurotoxic stimuli, ischemia and trauma) [1]. Microglia are the principal cells expressing IL-1β, but many other resident cells (including astrocytes and neurons) or invading cells are able to produce the cytokine [2]. When applied on healthy neurons, IL-1β does not cause damage or death; it induces a number of promoting factors [8]. There is evidence that IL-1β is necessary for proper remyelination of the CNS following death of mature oligodendrocytes since IL-1β−/− nerve fibers are unable to remyelinate properly after cuprizone-induced demyelination [15]. IL-1β contributes to sensory nerve regeneration in vivo following sciatic nerve injury [16,17]

Methods

Results

Conclusion