期刊
THERANOSTICS
卷 7, 期 4, 页码 855-875出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.17558
关键词
CXC chemokine 14 (CXCL14); regulatory T cells (Treg); immature dendritic cells (iDC); cerebral ischemia; hypoxia inducible factor 1 alpha (HIF-1 alpha)
资金
- Chen-Han Foundation for Education
- Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence [MOHW105-TDU-B-212-133019]
- China Medical University Hospital
- Academia Sinica Taiwan Biobank, Stroke Biosignature Project [BM10501010037]
- NRPB Stroke Clinical Trial Consortium [MOST 105-2325-B-039-005]
- Tseng-Lien Lin Foundation, Taichung, Taiwan
- Taiwan Brain Disease Foundation, Taipei, Taiwan
- Katsuzo and Kiyo Aoshima Memorial Funds, Japan
- China Medical University and Hospital [CMU104-S10, CMU104-S-15-03, DMR-104-054]
- Taiwan's National Science Council [NSC97-2314-B-039-036-MY3, NSC99-2632-B-039-001-MY3, NSC100-2314-B-039-002-MY3, NSC 101-2321-B-039-004, NSC101-2321-B-039-006, NSC101-2321-B-039-008, NSC102-2325-B-039-006, NSC102-2325-B-039-001, MOST 105-2314-B-039-011 -MY3]
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-1 alpha (HIF-1 alpha) 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.
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