title: Tollip is a critical mediator of cerebral ischaemia-reperfusion injury.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, People's Republic of China.
authors.forename: Mingchang
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.|Cardiovascular Research Institute, Wuhan University, People's Republic of China.
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.|Cardiovascular Research Institute, Wuhan University, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.|Cardiovascular Research Institute, Wuhan University, People's Republic of China.|College of Life Sciences, Wuhan University, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.|Cardiovascular Research Institute, Wuhan University, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.|Cardiovascular Research Institute, Wuhan University, People's Republic of China.
authors.forename: Ankang
authors.initials: A
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, People's Republic of China.|Cardiovascular Research Institute, Wuhan University, People's Republic of China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D064113:CRISPR-Cas Systems; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C410602:TOLLIP protein, human; C485837:Tollip protein, mouse; C539480:tollip protein, rat; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Akt; Tollip; apoptosis; knockout rat; stroke