title: Interleukin-23 Secreted by Activated Macrophages Drives γδT Cell Production of Interleukin-17 to Aggravate Secondary Injury After Intracerebral Hemorrhage.
abstract: Neuroinflammation plays a key role in intracerebral hemorrhage (ICH)-induced secondary brain injury, but the specific roles of peripheral inflammatory cells such as macrophages and lymphocytes remain unknown. The purpose of this study was to explore the roles of macrophages, T lymphocytes, and the cytokines they secrete as potential targets for treating secondary brain injury after ICH.
  
  
  
  Our results showed that peripheral macrophages and T lymphocytes successively infiltrated the brain, with macrophage counts peaking 1 day after ICH and T-lymphocyte counts peaking after 4 days. These peaks in cellular infiltration corresponded to increases in interleukin (IL)-23 and IL-17 expression, respectively. We found that hemoglobin from the hematoma activated IL-23 secretion by infiltrating macrophages by inducing the formation of toll-like receptor (TLR) 2/4 heterodimer. This increased IL-23 expression stimulated γδT-cell production of IL-17, which increased brain edema and neurologic deficits in the model mice as a proinflammatory factor. Finally, we found that sparstolonin B (SsnB) could ameliorate brain edema and neurologic deficits in ICH model mice via inhibition of TLR2/TLR4 heterodimer formation, and notably, SsnB interacted with myeloid differentiation factor 88 Arg196.
  
  
  
  Together, our results reveal the importance of the IL-23/IL-17 inflammatory axis in secondary brain injury after ICH and thus provide a new therapeutic target for ICH treatment.
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing, China.
authors.forename: Qiao-Li
authors.initials: QL
authors.lastname: Liang
authors.affiliation: Department of Anatomy, Histology and Embryology, Chengdu Medical College, Chengdu, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Meng
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Wen-Yao
authors.initials: WY
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Yuan-Rui
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Mao-Fan
authors.initials: MF
authors.lastname: Liao
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Qiu-Wen
authors.initials: QW
authors.lastname: Gong
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Basic Medical College, Zhengzhou University, Zhengzhou, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Key Laboratory of Neurorepair and Regeneration, Tianjin and Ministry of Education, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China yangqwmlys@hotmail.com yangqwmlys@163.com.
authors.forename: Qing-Wu
authors.initials: QW
authors.lastname: Yang
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000276:immunology*; D002543:Cerebral Hemorrhage / Q000276:immunology*; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000276:immunology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D006576:Heterocyclic Compounds, 4 or More Rings; D020381:Interleukin-17; D053759:Interleukin-23; D016692:Receptors, Antigen, T-Cell, gamma-delta; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C561322:sparstolonin B
keywords: IL‐17; IL‐23; TLR2; TLR4; intracerebral hemorrhage; lymphocyte; macrophage