Project Details
Projekt
Paracrine Interleukin 6 improves neuronal network rewiring after stroke
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 417284923
Stroke is the second leading cause of death and the leading cause of disability worldwide. Treatment is limited to a narrow time window of 4.5 h, but fewer than 10% of patients benefit from this, and many are left with severe, lasting disabilities. A treatment focused on improving regeneration and functional recovery in the long term would be of great benefit, indeed, the brain harbors endogenous mechanisms to improve neuronal network rewiring. Interleukin 6 (IL6) is associated with higher risk for atherosclerosis and stroke and increased blood IL6 levels correlate with worse outcome. However, other studies have reported IL6 in the acute phase of stroke is able to reduce lesion size. The pleiotropic effects of IL6 might be explained by complex signaling mechanisms that differ according to the cell type involved and the condition of the tissue microenvironment. According to the concept of the neurovascular niche, interaction of neurons, astrocytes, endothelial cells and oligodendrocytes are of high relevance for stroke recovery. We have shown that downstream IL6 signaling of endothelial Signal transducer and activator of transcription 3 (Stat3) is of high importance for remodeling of the extracellular matrix (ECM), promotion of angiogenesis, and functional recovery. We hypothesize that paracrine IL6 signaling within the neurovascular niche can improve neuronal network rewiring and functional recovery. In the proposed project, we will focus on the effects of IL6 on the damaged corticospinal tract (CST) and the ipsilateral supplemental sensory motor area (SMA) after stroke in mice. We generated a mouse model for cell specific and inducible expression of IL6 (FLEX-IL6). The secreted IL6 is subsequently detectable by microdialysis and a fused myc-tag. We will study the effects of IL6 within the neurovascular niche, secreted either behind the blood brain barrier by astrocytes or before by endothelial cells. This will be induced 2 days after stroke to focus on regenerative mechanisms, rather than preventing acute cell death. Wild type littermates or vehicle injection instead of tamoxifen will serve as controls and we will ensure equal lesion size between groups with MRI before IL6 induction. We will analyse the effects on functional recovery, angiogenesis and ECM remodelling. Pilot experiments with astrocytic secretion of IL6 identified a trend towards improved functional recovery. This strongly supports our hypothesis. IL6 acts on the CST and on the SMA (traceable by the fused myc-tag), when it is secreted by astrocytes. We will further explore this relationship by using laser capture micro-dissection to excise IL6 positive CST bundles or the ipsilateral SMA in order to characterize protein expression. Effects on network rewiring in the SMA and CST regeneration will be visualized by tract tracing methods, MRI connectivity analysis, MALDI imaging and pharmacogenetics inhibition (DREADD) methods.
DFG Programme
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