title: Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-tolerant mice.
abstract: Repetitive hypoxic preconditioning creates long-lasting, endogenous protection in a mouse model of stroke, characterized by reductions in leukocyte-endothelial adherence, inflammation, and infarct volumes. The constitutively expressed chemokine CXCL12 can be upregulated by hypoxia and limits leukocyte entry into brain parenchyma during central nervous system inflammatory autoimmune disease. We therefore hypothesized that the sustained tolerance to stroke induced by repetitive hypoxic preconditioning is mediated, in part, by long-term CXCL12 upregulation at the blood-brain barrier (BBB). In male Swiss Webster mice, repetitive hypoxic preconditioning elevated cortical CXCL12 protein levels, and the number of cortical CXCL12+ microvessels, for at least two weeks after the last hypoxic exposure. Repetitive hypoxic preconditioning-treated mice maintained more CXCL12-positive vessels than untreated controls following transient focal stroke, despite cortical decreases in CXCL12 mRNA and protein. Continuous administration of the CXCL12 receptor (CXCR4) antagonist AMD3100 for two weeks following repetitive hypoxic preconditioning countered the increase in CXCL12-positive microvessels, both prior to and following stroke. AMD3100 blocked the protective post-stroke reductions in leukocyte diapedesis, including macrophages and NK cells, and blocked the protective effect of repetitive hypoxic preconditioning on lesion volume, but had no effect on blood-brain barrier dysfunction. These data suggest that CXCL12 upregulation prior to stroke onset, and its actions following stroke, contribute to the endogenous, anti-inflammatory phenotype induced by repetitive hypoxic preconditioning.
authors.affiliation: 1 Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Uma Maheswari
authors.initials: UM
authors.lastname: Selvaraj
authors.affiliation: 1 Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sterling B
authors.initials: SB
authors.lastname: Ortega
authors.affiliation: 2 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Ruilong
authors.initials: R
authors.lastname: Hu
authors.affiliation: 2 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gilchrist
authors.affiliation: 1 Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Kong
authors.affiliation: 1 Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Partin
authors.affiliation: 1 Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Plautz
authors.affiliation: 4 Department of Medicine, Washington University, St Louis, MO, USA.
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
authors.affiliation: 2 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.|3 Department of Ophthalmology, Louisiana State University School of Medicine, New Orleans, LA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gidday
authors.affiliation: 1 Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Stowe
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D019194:Ischemic Preconditioning; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D020521:Stroke / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse
keywords: AMD3100; CXCR4; chemokine; hypoxic preconditioning; stroke