gms | German Medical Science

Objective: Upon brain trauma, a large number of inflammatory mediators are released in brain parenchyma which affects not only glial and inflammatory cells but also neurons and neuronal function. Some immune mediators appear to be released by neurons themselves, suggesting that they may have additional, non-immune roles in TBI. We have recently demonstrated that IL-13 is expressed by neurons and induced upon trauma; its physiological function in neurons and its effects on neurons upon trauma is unknown.

Methods: We have used confocal and super-resolution STED microscopy, fractionation technique and phosphor-array platforms, in combination with single-molecule in situ-mRNA hybridization to identify the neuronal sources of IL-13 and its effects on neuronal function.

Results: We show that IL-13 is a presynaptic protein, and IL-13Ra1 is a post-synaptic receptor in mice, rats, and human brain tissue, therefore showing that neurons are the major source of IL-13. Furthermore, we demonstrate that IL-13 is upregulated in neurons upon trauma and, exploiting in vivo chemogenetic (PSAM/PSEM) approaches, we show that IL-13 is upregulated upon increased neuronal activity through pathways converging on the elevation of neuronal nuclear Calcium. We show that IL-13 triggers a set of signal transduction events in neurons that lead to glutamate receptor phosphorylation, induction of presynaptic and postsynaptic plasticity, and the activation of plasticity-related and anti-apoptotic transcriptional responses in neurons. We use holotomography live imaging to demonstrate that low doses of IL-13 reduce neuronal vulnerability to excitotoxic death, but high doses are neutral or detrimental. Finally, we demonstrate the relevance of our experimental observations by showing the early and massive upregulation of IL-13 and IL-13Ra1 in cortical tissue and CSF from human TBI patients from two independent cohorts.

Conclusion: Our data reveal that IL-13 is a previously unrecognized physiological modulator of synaptic physiology of neuronal origin, with implications for the establishment of synaptic plasticity and the survival of neurons under injury conditions. We show that the human brain is exposed to high levels of IL-13 upon trauma, which may be protective but, in region of high concentration, may be detrimental. Thus IL-13 provide a new, dose-dependent neuroprotective pathway for therapeutic manipulation.