The role of TNF-α, ADAM17 and IL-13 in CNS injury and repair

SCI is devastating pathology associated with a significant impact on life expectancy and quality, as well as a considerable economic cost. To date there is no cure available; hence there is an urgent need to identify efficient therapies. In order to achieve this, it is important to clearly identify the temporal and spatial role of specific target molecules; it may well be that some molecules play a regenerative role during the acute phase, while a more harmful effect may be observed at later stages, or vice versa. In this thesis, we firstly examined the potential effects of the “antiinflammatory” cytokine IL-13 on neuroregenerative processes. We show that IL-13 is a potent promoter of neurite growth and neuronal survival in vitro (chapter 2). The data presented in this thesis, together with own in vivo data indicating beneficial effects of IL-13 after SCI, make IL-13 a promising candidate to promote regeneration after CNS injuries. However, more studies are needed to determine the optimal time window and dosage for IL- 13 application, as well as the possibility of co-application of IL-13 with other molecules. Secondly, we present evidence that anti-TNF-D therapies have a specific time window of effectiveness. TNF-D mRNA levels do not correlate with TNF-D protein levels, since an increase of TNF-D mRNA expression was observed during the acute phase after SCI., while protein levels were decreased. Interestingly, functional recovery of locomotion skills have been observed using anti-TNF-D drugs during the early acute phase. However, during the early chronic phase, blocking of TNF-D did not influence functional outcome as assayed by the BMS (chapter 3). Finally, we investigated the role of the metalloproteinase ADAM17 in the pathology of SCI. We are the first to show that ADAM17 displays a celldependent effect on survival, with ADAM17 inhibition mainly reducing the viability of microglial cells (in vitro and in vivo). In addition, ADAM17 was found to be involved in the promotion of neurite growth in cortical neuronal cultures, and importantly, ADAM17 inhibition decreased functional outcome after SCI (chapter 4). These promising results strongly suggest a therapeutic potential for ADAM17 as a modulator of microglial survival and activation to promote regeneration after CNS injury. Together, our findings justify further studies on the therapeutic potential of both IL-13 and ADAM17 in the treatment of CNS injuries.

Publication year:2013

Accessibility:Open