Abstract
BackgroundThe histocompatibility complex (MHC) class I expression in the central nervous system (CNS) regulates synaptic plasticity events during development and adult life. Its upregulation may be associated with events such as axotomy, cytokine exposition and changes in neuron electrical activity. Since IFNγ is a potent inducer of the MHC I expression, the present work investigated the importance of this pro-inflammatory cytokine in the synaptic elimination process in the spinal cord, as well as the motor recovery of IFN−/−, following peripheral injury.MethodsThe lumbar spinal cords of C57BL/6J (wild type) and IFNγ−/− (mutant) mice, subjected to unilateral sciatic nerve transection, were removed and processed for immunohistochemistry and real time RT-PCR, while the sciatic nerves from animals subjected to unilateral crush, were submitted to immunohistochemistry and electron microscopy for counting of the axons. Gait recovery was monitored using the Cat Walk system. Newborn mice astrocyte primary cultures were established in order to study the astrocytic respose in the absence of the IFNγ expression.ResultsIFNγ−/− mutant mice showed a decreased expression of MHC I and β2-microglobulin mRNA coupled with reduced synaptophysin immunolabelling in the lesioned spinal cord segment. Following unilateral nerve transection, the Iba-1 (ionized calcium binding adaptor molecule 1) and glial fibrillary acid protein (GFAP) reactivities increased equally in both strains. In vitro, the astrocytes demonstrated similar GFAP levels, but the proliferation rate was higher in the wild type mice. In the crushed nerves (distal stump), neurofilaments and p75NTR immunolabeling were upregulated in the mutant mice as compared to the wild type and an improvement in locomotor recovery was observed.ConclusionThe present results show that a lack of IFNγ affects the MHC I expression and the synaptic elimination process in the spinal cord. Such changes, however, do not delay peripheral nerve regeneration after nerve injury.
Highlights
The histocompatibility complex (MHC) class I expression in the central nervous system (CNS) regulates synaptic plasticity events during development and adult life
The results showed a significantly enhanced β2-microglobulin mRNA expression in the lesioned side of the wild type as compared to mutant animals (C57BL/6J, 2.17 ± 0.03; C57BL/6J IFNγ−/−, 1.4 ± 0.05; P < 0.05; Figure 2)
Synaptic covering was affected in IFNγ−/− mice but not glial reactivity In order to assess the changes in synaptic activity after peripheral lesion, the spinal cord sections were immunostained with synaptophysin
Summary
The histocompatibility complex (MHC) class I expression in the central nervous system (CNS) regulates synaptic plasticity events during development and adult life. Since IFNγ is a potent inducer of the MHC I expression, the present work investigated the importance of this pro-inflammatory cytokine in the synaptic elimination process in the spinal cord, as well as the motor recovery of IFN−/−, following peripheral injury. Reactive astrocytes and microglia are involved in the detachment of synaptic terminals [8,9] and the release of cytokines such as IFNγ and TNFα [10,11], which promote inflammatory responses and the expression of MHC I by glial cells [12]. IFNγ may affect neuronal differentiation and survival [15,16] In this sense, the authors recently demonstrated that the absence of IFNγ in mutant mice altered the synaptic elimination process that results in neuronal degeneration, suggesting a neuroprotective role for this cytokine in normal animals [17]
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