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Interleukin-6 promotes sprouting and functional recovery in lesioned organotypic hippocampal slice cultures
David Hakkoum1, Luc Stoppini, Dominique Muller
1Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland. david.hakkoum@medecine.unige.ch
Insights
Interleukin-6 (IL-6) promotes central nervous system (CNS) repair by enhancing axon regeneration after injury. Neutralizing IL-6 impairs functional recovery and growth-associated protein expression, highlighting its crucial role in CNS repair mechanisms.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Interleukin-6 (IL-6) is a pro-inflammatory cytokine implicated in central nervous system (CNS) injury.
- The specific role of IL-6 in axonal sprouting and regeneration within the brain remains largely unexplored.
Purpose of the Study:
- To investigate the effect of IL-6 on axonal sprouting and functional recovery following CNS injury in a mouse organotypic hippocampal slice culture model.
Main Methods:
- Transection of Schaffer collaterals in mouse organotypic hippocampal slice cultures.
- Monitoring functional recovery using multi-electrode array recordings of synaptic responses.
- Assessing growth-associated protein (GAP-43) expression levels.
- Utilizing IL-6 blocking antibodies and exogenous IL-6 administration.
- Co-culture experiments with fluorescently labeled neurons to visualize axonal growth.
Main Results:
- IL-6 neutralization significantly impaired functional recovery and reduced GAP-43 expression post-lesion.
- Exogenous IL-6 administration dose-dependently enhanced functional recovery and increased GAP-43 expression.
- IL-6 treatment promoted axonal growth across the lesion site in co-culture models.
Conclusions:
- IL-6 plays a critical role in promoting CNS repair by facilitating axon regeneration and functional recovery.
- Targeting IL-6 pathways may represent a therapeutic strategy for enhancing CNS repair after injury.
Abstract:
Interleukin (IL)-6 is a pro-inflammatory cytokine now widely recognized to contribute to the molecular events that follow CNS injury. Little is known, however, about its action on axonal sprouting and regeneration in the brain. We addressed this issue using the model of transection of Schaffer collaterals in mice organotypic hippocampal slice cultures. Transection of slice cultures was associated with a marked release of IL-6 that could be neutralized by an IL-6 blocking antibody. We monitored functional recovery across the lesion by recording synaptic responses using a multi-electrode array. We found that application of IL-6 antibodies to the cultures after lesioning significantly reduced functional recovery across the lesion. Furthermore, the level of expression of the 43-kDa growth-associated protein (GAP-43) was lower in slices treated with the IL-6 neutralizing antibody than in those treated with a control IgG. Conversely, addition of exogenous IL-6 to the culture medium resulted in a dose-dependent enhancement of functional recovery across the lesion and a higher level of expression of GAP-43. Co-culture of CA3 hemi-slices from thy1-YFP mice with CA1 hemi-slices from wild-type animals confirmed that IL-6-treated co-cultures exhibited an increased number of growing fluorescent fibres across the lesion site. Taken together these data indicate that IL-6 plays an important role in CNS repair mechanisms by promoting regrowth and axon regeneration.
