Tollip is a critical mediator of cerebral ischaemia-reperfusion injury.
Toll-like receptor (TLR) signalling plays an important role in regulating cerebral ischaemia-reperfusion (I/R) injury. Toll-interacting protein (Tollip) is an endogenous negative modulator of TLR signalling that is involved in several inflammatory diseases. Our previous study showed that Tollip inhibits overload-induced cardiac remodelling. However, the role of Tollip in neurological disease remains unknown. In the present study, we proposed that Tollip might contribute to the progression of stroke and confirmed this hypothesis. We found that Tollip expression was significantly increased in I/R-challenged brain tissue of humans, mice and rats in vivo and in primary neurons subjected to oxygen and glucose deprivation in vitro, indicating the involvement of Tollip in I/R injury. Next, using genetic approaches, we revealed that Tollip deficiency protects mice against I/R injury by attenuating neuronal apoptosis and inflammation, as demonstrated by the decreased expression of pro-apoptotic and pro-inflammatory genes and the increased expression of anti-apoptotic genes. By contrast, neuron-specific Tollip over-expression exerted the opposite effect. Mechanistically, the detrimental effects of Tollip on neuronal apoptosis and inflammation following I/R injury were largely mediated by the suppression of Akt signalling. Additionally, to further support our findings, a Tollip knockout rat strain was generated via CRISPR-Cas9-mediated gene inactivation. The Tollip-deficient rats were also protected from I/R injury, based on dramatic decreases in neuronal apoptosis and ischaemic inflammation through Akt activation. Taken together, our findings demonstrate that Tollip acts as a novel modulator of I/R injury by promoting neuronal apoptosis and ischaemic inflammation, which are largely mediated by suppression of Akt signalling.
['Li|Mingchang|M|', 'Feng|Bin|B|', 'Wang|Lang|L|', 'Guo|Sen|S|', 'Zhang|Peng|P|', 'Gong|Jun|J|', 'Zhang|Yan|Y|', 'Zheng|Ankang|A|', 'Li|Hongliang|H|']
D000818:Animals D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D001921:Brain D064113:CRISPR-Cas Systems D015687:Cell Hypoxia D002478:Cells, Cultured D004195:Disease Models, Animal D005947:Glucose D006801:Humans D020925:Hypoxia-Ischemia, Brain D018836:Inflammation Mediators D047908:Intracellular Signaling Peptides and Proteins D018345:Mice, Knockout D009474:Neurons D051057:Proto-Oncogene Proteins c-akt D034622:RNA Interference D051381:Rats D017207:Rats, Sprague-Dawley D055647:Rats, Transgenic D015427:Reperfusion Injury D015398:Signal Transduction D013997:Time Factors D014162:Transfection
Tollip stroke apoptosis Akt knockout rat