title: IL-17A contributes to brain ischemia reperfusion injury through calpain-TRPC6 pathway in mice.
abstract: Interleukin (IL)-17A plays an important role in the cerebral ischemia/reperfusion (I/R) injury. However, the mechanisms are still largely unknown. Calpain-transient receptor potential canonical (subtype) 6 (TRPC6) signaling pathway has been recently found to be implicated in brain I/R injury. However, their relationships with IL-17A remain unknown. This study aims to test whether this important signaling has correlation with IL-17A and how they led to the neuronal damage in I/R injury. In the present study, mice were subjected to middle cerebral artery occlusion (60 min) followed by reperfusion for different times. Infarct volumes and neurological deficits were examined. Real-time PCR (RT-PCR) and Western blotting were conducted to detect IL-17A expression in the penumbral brain tissue. Activation of calpain and expression of TRPC6 were also studied. We found that cerebral I/R significantly increased the levels of IL-17A at 1, 3 and 6 days after reperfusion in the penumbral area. IL-17A knockout or anti-IL-17A monoclonal antibody (mAb) significantly reduced whereas recombinant mouse-IL-17A (rIL-17A) increased the activation of calpain at 3 days after reperfusion. The calpain specific inhibitor calpeptin significantly increased TRPC6 expression. Brain injury and neurological deficits were largely abrogated by IL-17A knockout, anti-IL-17A mAb or calpeptin. Recombinant IL-17A treatment markedly increased I/R injury. In conclusion, IL-17A may promote brain I/R injury through the increase of calpain-mediated TRPC6 proteolysis. These results further outline a novel neuroprotective strategy with increased effectiveness for the inhibition of excess brain IL-17A in cerebral I/R injury.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: nathancx@hotmail.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: franklinyun@hust.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D050052:TRPC Cation Channels / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D013997:Time Factors
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C098680:Il17a protein, mouse; D020381:Interleukin-17; D011994:Recombinant Proteins; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C071482:calpeptin; D002154:Calpain
keywords: IL-17A; TRPC6; calpain; ischemic stroke; middle cerebral artery occlusion