Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-Tolerant mice

Uma Maheswari Selvaraj, Sterling B. Ortega, Ruilong Hu, Robert Gilchrist, Xiangmei Kong, Alexander Partin, Erik J. Plautz, Robyn S. Klein, Jeffrey M. Gidday, Ann M. Stowe

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)801-813
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number3
DOIs
StatePublished - Mar 1 2017

Fingerprint

Leukocytes
Up-Regulation
Ischemia
Stroke
Microvessels
Blood-Brain Barrier
Autoimmune Diseases of the Nervous System
CXCR4 Receptors
Transendothelial and Transepithelial Migration
Chemokine CXCL12
Natural Killer Cells
Proteins
Anti-Inflammatory Agents
Central Nervous System
Macrophages
Inflammation
Phenotype
Messenger RNA
Brain
JM 3100

Keywords

  • AMD3100
  • chemokine
  • CXCR4
  • hypoxic preconditioning
  • stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-Tolerant mice. / Selvaraj, Uma Maheswari; Ortega, Sterling B.; Hu, Ruilong; Gilchrist, Robert; Kong, Xiangmei; Partin, Alexander; Plautz, Erik J.; Klein, Robyn S.; Gidday, Jeffrey M.; Stowe, Ann M.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 37, No. 3, 01.03.2017, p. 801-813.

Research output: Contribution to journalArticle

Selvaraj, UM, Ortega, SB, Hu, R, Gilchrist, R, Kong, X, Partin, A, Plautz, EJ, Klein, RS, Gidday, JM & Stowe, AM 2017, 'Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-Tolerant mice', Journal of Cerebral Blood Flow and Metabolism, vol. 37, no. 3, pp. 801-813. https://doi.org/10.1177/0271678X16639327
Selvaraj, Uma Maheswari ; Ortega, Sterling B. ; Hu, Ruilong ; Gilchrist, Robert ; Kong, Xiangmei ; Partin, Alexander ; Plautz, Erik J. ; Klein, Robyn S. ; Gidday, Jeffrey M. ; Stowe, Ann M. / Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-Tolerant mice. In: Journal of Cerebral Blood Flow and Metabolism. 2017 ; Vol. 37, No. 3. pp. 801-813.
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