title: A20 Ameliorates Intracerebral Hemorrhage-Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination.
abstract: Reducing excessive inflammation is beneficial for the recovery from intracerebral hemorrhage (ICH). Here, the roles and mechanisms of A20 (TNFAIP3), an important endogenous anti-inflammatory factor, are examined in ICH. A20 expression in the PBMCs of ICH patients and an ICH mouse model was detected, and the correlation between A20 expression and neurologic deficits was analyzed. A20 expression was increased in PBMCs and was negatively related to the modified Rankin Scale score. A20 expression was also increased in mouse perihematomal tissues. A20-/-and A20-overexpressing mice were generated to further analyze A20 function. Compared with wild-type (WT) mice, A20-/-and A20-overexpressing mice showed significant increases and decreases, respectively, in hematoma volume, neurologic deficit score, mortality, neuronal degeneration, and proinflammatory factors. Moreover, WT-A20-/-parabiosis was established to explore the role of A20 in peripheral blood in ICH injury. ICH-induced damage, including brain edema, neurologic deficit score, proinflammatory factors, and neuronal apoptosis, was reduced in A20-/-parabionts compared with A20-/-mice. Finally, the interactions between TRAF6 and Ubc13 and UbcH5c were increased in A20-/-mice compared with WT mice; the opposite occurred in A20-overexpressing mice. Enhanced IκBα degradation and NF-κB activation were observed in A20-/-mice, but the results were reversed in A20-overexpressing mice. These results suggested that A20 is involved in regulating ICH-induced inflammatory injury in both the central and peripheral system and that A20 reduces ICH-induced inflammation by regulating TRAF6 polyubiquitination. Targeting A20 may thus be a promising therapeutic strategy for ICH.
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Zhaoyou
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Faxiang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Yuanrui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Wenyao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Maofan
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Duan
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Qiuwen
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Basic Medical College, Zhengzhou University, Zhengzhou 450000, China; and.
authors.forename: Ao
authors.initials: A
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; yangqwmlys@hotmail.com.
authors.forename: Qingwu
authors.identifier: 0000-0001-8540-6488
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002543:Cerebral Hemorrhage / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048029:TNF Receptor-Associated Factor 6; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3