title: Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis.
abstract: Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3DTR-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3β), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-β did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3β/PTEN axis.
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Wang
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiong
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Meng
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Wen-Yao
authors.initials: WY
authors.lastname: Zhu
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Mao-Fan
authors.initials: MF
authors.lastname: Liao
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Wu
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yuan-Rui
authors.initials: YR
authors.lastname: Yang
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Duan
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Qiu-Wen
authors.initials: QW
authors.lastname: Gong
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Yang
authors.affiliation: 2 Basic Medical College, Zhengzhou University, Zhengzhou, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Xiong
authors.affiliation: 3 Department of Anesthesiology/Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Qing-Wu
authors.initials: QW
authors.lastname: Yang
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000150:complications*; D018920:Coculture Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016753:Interleukin-10; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Intracerebral hemorrhage; T-cells; inflammation; macrophages; microglia