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PMID: 12122049 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 14 ·2002-07-15 ·Pages 5865-78

Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Höllt V, Schulz S

Abstract

The chemoattractant stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) are key modulators of immune function. In the developing brain, SDF-1 is crucial for neuronal guidance; however, cerebral functions of SDF-1/CXCR4 in adulthood are unclear. Here, we examine the cellular expression of SDF-1 isoforms and CXCR4 in the brain of mice receiving systemic lipopolysaccharide (LPS) or permanent focal cerebral ischemia. CXCR4 mRNA was constitutively expressed in cortical and hippocampal neurons and ependymal cells. Hippocampal neurons targeted the CXCR4 receptor to their somatodendritic and axonal compartments. In cortex and hippocampus, CXCR4-expressing neurons exhibited an overlapping distribution with neurons expressing SDF-1 transcripts. Although neurons synthesized SDF-1alpha mRNA, the SDF-1beta isoform was selectively expressed by endothelial cells of cerebral microvessels. LPS stimulation dramatically decreased endothelial SDF-1beta mRNA expression throughout the forebrain but did not affect neuronal SDF-1alpha. After focal cerebral ischemia, SDF-1beta expression was selectively increased in endothelial cells of penumbral blood vessels and decreased in endothelial cells of nonlesioned brain areas. In the penumbra, SDF-1beta upregulation was associated with a concomitant infiltration of CXCR4-expressing peripheral blood cells, including macrophages. Neuronal SDF-1alpha was transiently downregulated and neuronal CXCR4 was transiently upregulated in the nonlesioned cerebral cortex in response to ischemia. Although endothelial SDF-1beta may control cerebral infiltration of CXCR4-carrying leukocytes during cerebral ischemia, the neuronal SDF-1alpha/CXCR4 system may contribute to ischemia-induced neuronal plasticity. Thus, the isoform-specific regulation of SDF-1 expression modulates neurotransmission and cerebral infiltration via distinct CXCR4-dependent pathways.

MeSH Terms
Animals Brain/blood supply,metabolism Brain Ischemia/immunology,metabolism Cell Line Chemokine CXCL12 Chemokines, CXC/genetics,metabolism Chemotaxis, Leukocyte/physiology Endothelium, Vascular/cytology,metabolism Humans Immunohistochemistry In Situ Hybridization Lipopolysaccharides/pharmacology Male Mice Mice, Inbred Strains Neuronal Plasticity/physiology Neurons/cytology,metabolism Organ Specificity Protein Isoforms/metabolism RNA, Messenger/metabolism Rats Rats, Wistar Receptors, CXCR4/metabolism
Chemicals
CXCL12 protein, human Chemokine CXCL12 Chemokines, CXC Cxcl12 protein, mouse Lipopolysaccharides Protein Isoforms RNA, Messenger Receptors, CXCR4
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Stumm Ralf K
Institute of Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
Rummel Jutta
Junker Vera
Culmsee Carsten
Pfeiffer Manuela
Krieglstein Josef
Höllt Volker
Schulz Stefan
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
20026609
Published
2002-07-15
Pages
5865-78
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757949
Subset
IM
External Links
PubMed source DOI: 20026609 PMC Full Text View journal details
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