title: A Crucial Role of CXCL14 for Promoting Regulatory T Cells Activation in Stroke.
abstract: Inflammatory processes have a detrimental role in the pathophysiology of ischemic stroke. However, little is known about the endogenous anti-inflammatory mechanisms in ischemic brain. Here, we identify CXCL14 as a critical mediator of these mechanisms. CXCL14 levels were upregulated in the ischemic brains of humans and rodents. Moreover, hypoxia inducible factor-1α (HIF-1α) drives hypoxia- or cerebral ischemia (CI)-dependent CXCL14 expression via directly binding to the CXCL14 promoter. Depletion of CXCL14 inhibited the accumulation of immature dendritic cells (iDC) or regulatory T cells (Treg) and increased the infarct volume, whereas the supplementation of CXCL14 had the opposite effects. CXCL14 promoted the adhesion, migration, and homing of circulating CD11c+iDC to the ischemic tissue via the upregulation of the cellular prion protein (PrPC), PECAM-1, and MMPs. The accumulation of Treg in ischemic areas of the brain was mediated through a cooperative effect of CXCL14 and iDC-secreted IL-2-induced Treg differentiation. Interestingly, CXCL14 largely promoted IL-2-induced Treg differentiation. These findings indicate that CXCL14 is a critical immunomodulator involved in the stroke-induced inflammatory reaction. Passive CXCL14 supplementation provides a tractable path for clinical translation in the improvement of stroke-induced neuroinflammation.
authors.affiliation: Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan 40421.
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.affiliation: Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan, Republic of China.; Translational Medicine Research Center and Department of Neurology, China Medical University & Hospital, Taichung, Taiwan, Republic of China.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Liu
authors.affiliation: Translational Medicine Research Center and Department of Neurology, China Medical University & Hospital, Taichung, Taiwan, Republic of China.
authors.forename: Chen-Huan
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Translational Medicine Research Center and Department of Neurology, China Medical University & Hospital, Taichung, Taiwan, Republic of China.
authors.forename: Sophie Wei
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan, Republic of China.
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.affiliation: Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan, Republic of China.; Department of Biomedical Informatics, Asia University, No. 500, Lioufeng Road, Taichung, Taiwan, Republic of China.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan, Republic of China.; Translational Medicine Research Center and Department of Neurology, China Medical University & Hospital, Taichung, Taiwan, Republic of China.
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
mesh_terms: D000818:Animals; D019743:Chemokines, CXC / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000503:physiopathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C118056:CXCL14 protein, human; D019743:Chemokines, CXC
keywords: CXC chemokine 14 (CXCL14); cerebral ischemia; hypoxia inducible factor 1α (HIF-1α).; immature dendritic cells (iDC); regulatory T cells (Treg)