title: Lipocalin-2 released in response to cerebral ischaemia mediates reperfusion injury in mice.
abstract: Thrombolysis remains the only effective therapy to reverse acute ischaemic stroke. However, delayed treatment may cause serious complications including hemorrhagic transformation and reperfusion injury. The level of lipocalin-2 (LCN2) is elevated in the plasma of ischaemic stroke patients, but its role in stroke is unknown. Here, we show that LCN2 was acutely induced in mice after ischaemic stroke and is an important mediator of reperfusion injury. Increased levels of LCN2 were observed in mouse serum as early as 1 hr after transient middle cerebral artery occlusion (tMCAO), reaching peak levels at 23 hrs. LCN2 was also detected in neutrophils infiltrating into the ipsilateral hemisphere, as well as a subset of astrocytes after tMCAO, but not in neurons and microglia. Stroke injury, neurological deficits and infiltration of immune cells were markedly diminished in LCN2 null mice after tMCAO, but not after permanent MCAO (pMCAO). In vitro, recombinant LCN2 protein induced apoptosis in primary cultured neurons in a dose-dependent manner. Our results demonstrate that LCN2 is a neurotoxic factor secreted rapidly in response to cerebral ischaemia, suggesting its potential usage as an early stroke biomarker and a novel therapeutic target to reduce stroke-reperfusion injury.
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors.forename: Guona
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors.forename: Yi-Chinn
authors.initials: YC
authors.lastname: Weng
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Whaley
authors.affiliation: Department of Cellular and Molecular Medicine and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: McCrae
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Chou
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000150:complications; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000473:pathology; D020556:Neutrophil Infiltration; D015513:Oncogene Proteins / Q000097:blood / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology; D020521:Stroke / Q000097:blood / Q000150:complications
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D027701:Organic Cation Transport Proteins; C071332:Lcn2 protein, mouse
keywords: biomarker; lipocalin-2; neutrophil; reperfusion injury; stroke